Skip to main content

Advertisement

SpringerLink
Log in

Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

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

Abstract

Objective

To examine the discriminative stimulus effects of the cannabinoid CB1 receptor (CB1R) antagonist/inverse agonist rimonabant (SR141716A) using a discriminated taste aversion (DTA) procedure.

Materials and methods

Groups of rats were trained to discriminate between drug (5.6 or 3 mg/kg) and vehicle in DTA (t′ = 20 min). The 30-min drinking opportunity after rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental (EXP) animals. When offered fluid after vehicle pretreatment, EXP animals subsequently were given intraperitoneal saline (NaCl, 10 ml/kg). Post-drinking treatment for controls (CONT) was NaCl irrespective of the pretreatment condition (rimonabant or vehicle). Tests examined other doses and drugs (t′ = 20 min).

Results

The rimonabant analog AM251 (1 to 5.6 mg/kg) substituted for rimonabant. AM281 also appeared to substitute, but interpretation is complicated by unconditioned effects (drinking suppressed also in the CONT group). The CB2R antagonists SR144528 (18 and 30 mg/kg), AM630 (1 to 10 mg/kg), and the CB1R agonist methanandamide (mAEA, 3 and 10 mg/kg) did not substitute. There was a dose-related attenuation of the rimonabant-induced suppression of saccharin drinking when Δ9-tetrahydrocannabinol (Δ9-THC; 0.3 to 5.6 mg/kg), but not mAEA (1 to 10 mg/kg), was given together with rimonabant (3 mg/kg). Unconditioned effects occurred with the mAEA–rimonabant combination, not evident for combinations of rimonabant and Δ9-THC. mAEA (10 mg/kg) plus AM251 (5.6 mg/kg) resulted in strong unconditioned effects.

Conclusion

Rimonabant induces a discriminative stimulus in DTA that continues to show potential for further examination of cannabinoid receptor antagonism.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Abadji V, Lin S, Taha G, Griffin G, Stevenson LA, Pertwee RG, Makriyannis A (1994) (R)-methanandamide: a chiral novel anandamide possessing higher potency and metabolic stability. J Med Chem 37:1889–1893

    Article  PubMed  CAS  Google Scholar 

  • Balster RL, Prescott WR (1992) Δ9-Tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neurosci Biobehav Rev 16:55–62

    Article  PubMed  CAS  Google Scholar 

  • Baskfield CY, Martin BR, Wiley JL (2004) Differential effects of Δ9-tetrahydrocannabinol and methanandamide in CB1 knockout and wild-type mice. J Pharmacol Exp Ther 309:86–91

    Article  PubMed  CAS  Google Scholar 

  • Colpaert FC, Niemegeers CJ, Janssen PA (1980) Factors regulating drug cue sensitivity: the effect of training dose in fentanyl-saline discrimination. Neuropharmacology 19:705–713

    Article  PubMed  CAS  Google Scholar 

  • De Vry J, Jentzsch KR (2003) Intrinsic activity estimation of cannabinoid CB1 receptor ligands in a drug discrimination paradigm. Behav Pharmacol 14:471–476

    PubMed  Google Scholar 

  • Gatley SJ, Lan R, Volkow ND, Pappas N, King P, Wong CT, Gifford AN, Pyatt B, Dewey SL, Makriyannis A (1998) Imaging the brain marijuana receptor: development of a radioligand that binds to cannabinoid CB1 receptors in vivo. J Neurochem 70:417–423

    PubMed  CAS  Google Scholar 

  • Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23

    Article  PubMed  CAS  Google Scholar 

  • Greenberg I, Kuhn DM, Appel JB (1975) Behaviorally induced sensitivity to the discriminable properties of LSD. Psychopharmacologia 43:229–232

    Article  PubMed  CAS  Google Scholar 

  • Hàjos N, Freund TF (2002) Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology 43:503–510

    Article  PubMed  Google Scholar 

  • Howlett AC (2004) Efficacy in CB1 receptor-mediated signal transduction. Br J Pharmacol 142:1209–1218

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Järbe TUC (1989) Discrimination learning with drug stimuli: methods and applications. In: Boulten AA, Baker GB, Greenshaw AJ (eds) Neuromethods, vol 13. Psychopharmacology, Humana Press, Clifton, NJ, pp 513–563

    Google Scholar 

  • Järbe TUC, Lamb RJ (1995) Discriminated conditioned taste aversion for studying multi-elemental stimulus control. Behav Pharmacol 6:149–155

    PubMed  Google Scholar 

  • Järbe TUC, Lamb RJ (1999) Effects of lithium dose (UCS) on the acquisition and extinction of a discriminated morphine aversion: tests with morphine and Δ9-THC. Behav Pharmacol 10:349–358

    Article  PubMed  Google Scholar 

  • Järbe TUC, Mathis DA (1992) Dissociative and discriminative stimulus functions of cannabinoids and cannabimimetics. In: Bartke A, Murphy L (eds) Marijuana/cannabinoids: neurobiology and neurophysiology. CRC Press, Boca Raton, FL, pp 425–459

    Google Scholar 

  • Järbe TUC, Swedberg MDB (1998) Discriminative stimulus functions of CNS sedative drugs assessed by drug versus drug discrimination procedures in gerbils. Psychopharmacology (Berl) 135:201–212

    Article  Google Scholar 

  • Järbe TUC, Sheppard R, Lamb RJ, Makriyannis A, Lin S, Goutopoulos A (1998) Effects of delta-9-tetrahydrocannabinol and (R)-methanandamide on open-field behavior in rats. Behav Pharmacol 9:169–174

    PubMed  Google Scholar 

  • Järbe TUC, Lamb RJ, Lin S, Makriyannis A (2001) (R)-methanandamide and Δ9-THC as discriminative stimuli in rats: tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide. Psychopharmacology (Berl) 156:369–380

    Article  Google Scholar 

  • Järbe TUC, Andrzejewski ME, DiPatrizio NV (2002) Interactions between the CB1 receptor agonist Δ9-THC and the CB1 receptor antagonist SR-141716 in rats: open-field revisited. Pharmacol Biochem Behav 73:911–919

    Article  PubMed  Google Scholar 

  • Järbe TUC, DiPatrizio NV, Li C, Makriyannis A (2003a) The cannabinoid receptor antagonist SR-141716 does not readily antagonize open-field effects induced by the cannabinoid receptor agonist (R)-methanandamide in rats. Pharmacol Biochem Behav 75:809–821

    Article  PubMed  CAS  Google Scholar 

  • Järbe TUC, Lamb RJ, Liu Q, Makriyannis A (2003b) (R)-methanandamide and Δ9-THC induced operant rate decreases in rats are not readily antagonized by SR-141716A. Eur J Pharmacol 466:121–127

    Article  PubMed  CAS  Google Scholar 

  • Järbe TUC, Harris MY, Li C, Liu Q, Makriyannis A (2004) Discriminative stimulus effects in rats of SR-141716 (rimonabant), a cannabinoid CB1 receptor antagonist. Psychopharmacology (Berl) 177:35–45

    Article  CAS  Google Scholar 

  • Järbe TUC, Lamb RJ, Liu Q, Makriyannis A (2006a) Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Δ9-THC or (R)-methanandamide (AM-356). Psychopharmacology (Berl) 188:315–323

    Article  CAS  Google Scholar 

  • Järbe TUC, Liu Q, Makriyannis A (2006b) Antagonism of discriminative stimulus effects of Δ9-THC and (R)-methanandamide in rats. Psychopharmacology (Berl) 184:36–45

    Article  CAS  Google Scholar 

  • Kautz MA, Geter B, McBride SA, Mastropaolo JP, Riley AL (1989) Naloxone as a stimulus for drug discrimination learning. Drug Dev Res 16:317–326

    Article  CAS  Google Scholar 

  • Kirk RE (1968) Experimental design: procedures for the behavioral sciences, 2nd edn. Brooks/Cole, Belmont, CA

    Google Scholar 

  • Lamb RJ, Järbe TUC (1997) Multielemental stimulus control: effects of saccharin concentration on a discriminated morphine-saccharin taste aversion. Exp Clin Psychopharmacol 5:123–129

    Article  PubMed  CAS  Google Scholar 

  • Lucki I (1988) Rapid discrimination of the stimulus properties of 5-hydroxytryptamine agonists using conditioned taste aversion. J Pharmacol Exp Ther 247:1120–1127

    PubMed  CAS  Google Scholar 

  • Lan R, Liu Q, Fan P, Lin S, Fernando SR, McCallion D, Pertwee RG, Makriyannis A (1999) Structure–activity relationship of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42:776–779

    Article  Google Scholar 

  • McMahon LR (2006a) Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Δ9-tetrahydrocannabinol. J Pharmacol Exp Ther 319:1211–1218

    Article  PubMed  CAS  Google Scholar 

  • McMahon LR (2006b) Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9-tetrahydrocannabinol. Psychopharmacology (Berl) 188:306–314

    Article  CAS  Google Scholar 

  • McMahon LR, Koek W (2007) Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice. Eur J Pharmacol 569:70–76

    Article  PubMed  CAS  Google Scholar 

  • Mastropaolo J, Riley AL (1990) Drug discrimination studies in animals. In: Deutsch SI, Weizman A, Weizman R (eds) Application of basic neuroscience to child psychiatry. Plenum, New York, pp 125–140

    Google Scholar 

  • Malan TP Jr., Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, Porreca F, Makriyannis A (2001) CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 93:239–245

    Article  PubMed  CAS  Google Scholar 

  • Mansbach RS, Rovetti CC, Winston EN, Lowe JA (1996) Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats. Psychopharmacology (Berl) 124:315–322

    Article  CAS  Google Scholar 

  • Melton PM, Kopman JA, Riley AL (1993) Cholecystokinin as a stimulus in drug discrimination learning. Pharmacol Biochem Behav 44:249–252

    Article  PubMed  CAS  Google Scholar 

  • National Institutes of Health (1996) Principles of animal laboratory care. National Academy Press, Washington, DC

    Google Scholar 

  • Overton DA (1979) Drug discrimination training with progressively lowered doses. Science 205:720–721

    Article  PubMed  CAS  Google Scholar 

  • Overton DA, Leonard WR, Merkle DA (1986) Methods for measuring the strength of discriminable drug effects. Neurosci Biobehav Rev 10:251–263

    Article  PubMed  CAS  Google Scholar 

  • Oz M (2006) Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids. Pharmacol Ther 111:114–144

    Article  PubMed  CAS  Google Scholar 

  • Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462

    Article  PubMed  CAS  Google Scholar 

  • Pèrio A, Rinaldi-Carmona M, Maruani J, Barth F, Le Fur G, Soubrié P (1996) Central mediation of the cannabinoid cue: activity of a selective CB1 antagonist, SR 141716A. Behav Pharmacol 7:65–71

    Article  PubMed  Google Scholar 

  • Pertwee R, Griffin G, Fernando S, Li X, Hill A, Makriyannis A (1995) AM630, a competitive cannabinoid antagonist. Life Sci 56:1949–1955

    Article  PubMed  CAS  Google Scholar 

  • Riley AL (1997) Drug discrimination learning: assessment of opioid receptor pharmacology. In: Learning, motivation, and cognition: the functional behaviorism of Robert C. Bolles. American Psychological Association, Washington, DC, pp 225–254

    Chapter  Google Scholar 

  • Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Néliat G, Caput D, Ferrara P, Soubrié P, Breliére JC, LeFur G (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244

    Article  PubMed  CAS  Google Scholar 

  • Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, Oustric D, Sarran M, Bouaboula M, Calandra B, Portier M, Shire D, Breliere JC, Le Fur GL (1998) SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther 284:644–650

    PubMed  CAS  Google Scholar 

  • 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 16:405–413

    Article  PubMed  CAS  Google Scholar 

  • Sidman M (1960) Tactics of scientific research—evaluating experimental data in psychology. Basic Books, New York, NY

    Google Scholar 

  • Solinas M, Panlilio LV, Justinova Z, Yasar S, Goldberg SR (2006) Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats. Nat Protoc 1:1194–1206

    Article  PubMed  CAS  Google Scholar 

  • Solinas M, Tanda G, Justinova Z, Wertheim CE, Yasar S, Piomelli D, Vadivel SK, Makriyannis A, Goldberg SR (2007) The endogenous cannabinoid anandamide produces Δ9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport. J Pharmacol Exp Ther 321:370–380

    Article  PubMed  CAS  Google Scholar 

  • Stevenson GW, Pournaghash S, Riley AL (1992) Antagonism of drug discrimination learning within the conditioned taste aversion procedure. Pharmacol Biochem Behav 41:245–249

    Article  PubMed  CAS  Google Scholar 

  • Swedberg MDB, Järbe TUC (1982) Morphine cue saliency: limits of discriminability and third state perception by pigeons. In: Colpaert FC, Slangen JL (eds) Drug discrimination: applications in CNS pharmacology. Elsevier, Amsterdam, pp 147–164

    Google Scholar 

  • Vann RE, Cook CD, Martin BR, Wiley JL (2007) Cannabimimetic properties of ajulemic acid. J Pharmacol Exp Ther 320:678–686

    Article  PubMed  CAS  Google Scholar 

  • Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332

    Article  PubMed  CAS  Google Scholar 

  • Vlachou S, Nomikos GG, Panagis G (2005) CB1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat. Psychopharmacology (Berl) 179:498–508

    Article  CAS  Google Scholar 

  • Wiley JL (1999) Cannabis: discrimination of “internal bliss”? Pharmacol Biochem Behav 64:257–260

    Article  PubMed  CAS  Google Scholar 

  • Wiley JL, Lowe JA, Balster RL, Martin BR (1995) Antagonism of the discriminative stimulus effects of Δ9-tetrahydrocannabinol in rats and rhesus monkeys. J Pharmacol Exp Ther 275:1–6

    PubMed  CAS  Google Scholar 

  • Wiley JL, LaVecchia KL, Karp NE, Kulasegram S, Mahadevan A, Razdan RK, Martin BR (2004) A comparison of the discriminative stimulus effects of Δ9-tetrahydrocannabinol and O-1812, a potent and metabolically stable anandamide analog, in rats. Exp Clin Psychopharmacol 12:173–179

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank NIDA, Bethesda, MD, for supplies of Δ9-THC, rimonabant, and SR142845. We thank Ms. M. Harris for technical assistance and Dr. J. Troisi, Ms. S. Tai, and Mr. B. LeMay as well as three anonymous reviewers for comments on the manuscript. Supported by NIDA Grants DA 09064, 00253, and 13429 (Philadelphia, PA), 03801, 9158, 7215, and 00493 (Storrs, CT and Boston, MA).

Author information

Authors and Affiliations

  1. Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA, 19122, USA

    Torbjörn U. C. Järbe

  2. Center for Drug Discovery and Departments of Pharmaceutical Sciences and Molecular and Cell Biology, University of Connecticut, U-92, Storrs, CT, 06269, USA

    Chen Li, Subramanian K. Vadivel & Alexandros Makriyannis

  3. Center for Drug Discovery (CDD), Department of Pharmaceutical Sciences, Northeastern University, 116 Mugar Hall, 360 Huntington Ave, Boston, MA, 02115, US, A

    Torbjörn U. C. Järbe, Subramanian K. Vadivel & Alexandros Makriyannis

Authors
  1. Torbjörn U. C. Järbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Subramanian K. Vadivel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandros Makriyannis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Torbjörn U. C. Järbe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Järbe, T.U.C., Li, C., Vadivel, S.K. et al. Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats. Psychopharmacology 198, 467–478 (2008). https://doi.org/10.1007/s00213-008-1076-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1076-0

Keywords

Search

Navigation