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Discriminative stimulus effects in rats of SR-141716 (rimonabant), a cannabinoid CB1 receptor antagonist

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Abstract

Objective

To examine the discriminative stimulus effects of (i) the cannabinoid CB1 receptor antagonist SR-141716 (SR, 5.6 mg/kg) and vehicle, and (ii) the cannabinoid receptor agonist Δ9-THC (THC, 1.8 mg/kg) and vehicle using a discriminated taste aversion (DTA) procedure.

Methods

Two groups of rats (n=6) were trained to discriminate between these drugs and vehicle in DTA (t′=20 min). The 30-min drinking bout of tap water following drug (SR or THC) treatment was followed by an injection of lithium chloride (LiCl, 120 mg/kg) in the experimental animals. When offered water after vehicle pretreatment, experimental animals subsequently were given IP saline (NaCl, 10 ml/kg). Post-drinking treatment for controls (n=6) was NaCl, irrespective of the pretreatment condition (SR, THC or vehicle). Additional water was provided during the afternoon (30 min) with no other manipulations. Food was available ad lib at all times. When the discriminations were established other doses and drugs were examined (t′=20 min). In testing there were no post-drinking treatments.

Results

The SR-related analog AM-251 (dose range: 1–5.6 mg/kg) substituted for SR, whereas other drugs such as the cannabinoid CB2 receptor antagonist SR-144528 (3 and 10 mg/kg), THC (1–10 mg/kg), flumazenil (1–10 mg/kg), naloxone (1–10 mg/kg), morphine (10 and 18 mg/kg) and d-amphetamine (1 and 3 mg/kg) did not. There was a dose-related attenuation of SR-induced suppression of drinking when THC (1.8–10 mg/kg) was given together with SR (5.6 mg/kg). In the THC trained rats, SR (1–10 mg/kg), morphine (10 and 18 mg/kg) and d-amphetamine (1 and 3 mg/kg) did not substitute for THC. SR (1 mg/kg) attenuated the THC (1.8 mg/kg) induced suppression of drinking. Together with 3 mg/kg SR and 1.8 mg/kg THC, drinking was roughly equally suppressed in both the experimental group and the controls.

Conclusion

SR-141716 induces a discriminative stimulus complex in DTA that shows potential for further examination of cannabinoid receptor antagonism.

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References

  • Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelat M, Soubrié P, Le Fur G (1997) Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 132:104–106

    Google Scholar 

  • Ator NA, Griffiths RR (1983) Lorazepam and pentobarbital drug discrimination in baboons: cross-drug generalization and interaction with Ro 15-1788. J Pharmacol Exp Ther 226:776–782

    CAS  PubMed  Google Scholar 

  • Balster RL, Prescott WR (1992) Delta-9-tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neurosci Biobehav Rev 16:55–62

    CAS  PubMed  Google Scholar 

  • Bass CE, Griffin G, Grier M, Mahadevan A, Razdan RK, Martin BR (2002) SR-141716A-induced stimulation of locomotor activity: a structure-activity relationship study. Pharmacol Biochem Behav 74:31–40

    Article  CAS  PubMed  Google Scholar 

  • Beardsley PM, Dance ME, Balster RL, Munzar P (2002) Evaluation of the reinforcing effects of the cannabinoid CB1 receptor antagonist, SR141716, in rhesus monkeys. Eur J Pharmacol 435:209–216

    Article  CAS  PubMed  Google Scholar 

  • Berry EM, Mechoulam R (2002) Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol Ther 95:185–190

    Article  CAS  PubMed  Google Scholar 

  • Colpaert FC, Janssen PAJ (1984) Agonist and antagonist effects of prototype opiate drugs in rats discriminating fentanyl from saline: characteristics of partial generalization. J Pharmacol Exp Ther 230:193–199

    CAS  PubMed  Google Scholar 

  • Compton DR, Aceto MD, Lowe J, Martin BR (1996) In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta-9-tetrahydrocannabinol-induced responses and apparent agonist activity. J Pharmacol Exp Ther 277:586–594

    CAS  PubMed  Google Scholar 

  • Costa B, Colleoni M (1999) SR141716 induces in rats a behavioral pattern opposite to that of CB1 receptor agonists. Acta Pharmacol Sin 20:1103–1108

    CAS  Google Scholar 

  • Darmani NA, Pandya DK (2000) Involvement of other neurotransmitters in behaviors induced by the cannabinoid CB1 receptor antagonist SR 141716A in naive mice. J Neural Transm 107:931–945

    Article  CAS  PubMed  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 

  • Evans SM, Johanson CE (1989) Discriminative stimulus properties of midazolam in the pigeon. J Pharmacol Exp Ther 284:29–38

    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  CAS  PubMed  Google Scholar 

  • Freedland CS, Sharpe AL, Samson HH, Porrino LJ (2001) Effects of SR141716 on ethanol and sucrose self-administration. Alcohol Clin Exp Res 25:277–282

    CAS  PubMed  Google Scholar 

  • Goutopoulos A, Makriyannis A (2002) From cannabis to cannabinergics: new therapeutic opportunities. Pharmacol Ther 95:103–117

    Article  CAS  Google Scholar 

  • Griffin G, Wray EJ, Tao Q, McAllister SD, Rorrer WK, Aung M, Martin BR, Abood ME (1999) Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. Eur J Pharmacol 377:117–125

    Article  CAS  PubMed  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 

  • Hiltunen AJ, Järbe TUC (1986) Discrimination of Ro 11-6896, chlordiazepoxide, and ethanol in gerbils: generalization and antagonism tests. Psychopharmacology 89:284–290

    Google Scholar 

  • Holtzman SG (1985) Drug discrimination studies. Drug Alcohol Depend 14:263–282

    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 

  • Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 58:322–328

    CAS  PubMed  Google Scholar 

  • Hungund BL, Basavarajappa BS, Vadasz C, Kunos G, de Fonseca FR, Colombo G, Serra S, Parsons L, Koob GF (2002) Ethanol, endocannabinoids, and the cannabinoidergic signaling system. Alcohol Clin Exp Res 26:565–574

    Article  CAS  PubMed  Google Scholar 

  • Janoyan JJ, Crim JL, Darmani NA (2002) Reversal of SR 141716A-induced head-twitch and ear-scratch responses in mice by Δ9-THC and other cannabinoids. Pharmacol Biochem Behav 71:155–162

    Google Scholar 

  • Järbe TUC (1978) Discriminative effects of morphine in the pigeon. Pharmacol Biochem Behav 9:411–416

    Google Scholar 

  • Järbe TUC (1982) Discriminative stimulus properties of d-amphetamine in pigeons. Pharmacol Biochem Behav 17:671–675

    Article  PubMed  Google Scholar 

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

  • Järbe TUC, Henriksson BG (1973) Acute effects of two tetrahydrocannabinols (delta-9-THC and delta-8-THC) on water intake in water deprived rats: implications for behavioral studies on marijuana compounds. Psychopharmacologia 30:315–322

    PubMed  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

    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, Boca Raton, pp 425–459

  • Järbe TUC, Rollenhagen C (1978) Morphine as a discriminative cue in gerbils: drug generalization and antagonism. Psychopharmacology 58:271–275

    PubMed  Google Scholar 

  • Järbe TUC, Lamb RJ, Makriyannis A, Lin S, Goutopoulos A (1998) Δ9-THC training dose as a determinant for (R)-methanandamide generalization in rats. Psychopharmacology 140:519–522

    Google Scholar 

  • Järbe TUC, Lamb RJ, Lin S, Makriyannis A (2000) Δ9-THC training dose as a determinant for (R)-methanandamide generalization in rats: a systematic replication. Behav Pharmacol 11:81–86

    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 156:369–380

    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  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  Google Scholar 

  • Johansson J, Järbe TUC, Henriksson BG (1975) Acute and subchronic influences of tetrahydrocannabinols on water and food intake, body weight, and temperature in male rats. T-I-T-J Life Sci 5:17–27

    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

    CAS  Google Scholar 

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

    Google Scholar 

  • Kirkham TC (2003) Endogenous cannabinoids: a new target in the treatment of obesity. Am J Physiol Integr Comp Physiol 284:R343–R344

    CAS  Google Scholar 

  • Kirkham TC, Williams CM (2001) Synergistic effects of opioid and cannabinoid antagonists on food intake. Psychopharmacology 153:267–270

    Google Scholar 

  • Lallemand F, Soubrié PH, De Witte PH (2001) Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic ethanol administration. Alcohol Clin Exp Res 25:1317–1323

    Article  CAS  PubMed  Google Scholar 

  • Lamb RJ, Henningfield JE (1994) Human d-amphetamine drug discrimination: methamphetamine and hydromorphone. J Exp Anal Behav 61:169–180

    CAS  PubMed  Google Scholar 

  • Lan R, Fernando S, Fan P, McCallion D, Liu Q, Pertwee R, Makriyannis A (1999) Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42:769–776

    Article  CAS  PubMed  Google Scholar 

  • Lelas S, Gerak LR, France CP (1999) Discriminative-stimulus effects of triazolam and midazolam in rhesus monkeys. Behav Pharmacol 10:39–50

    CAS  PubMed  Google Scholar 

  • Lelas S, Spealman RD, Rowlett JK (2000) Using behavior to elucidate receptor mechanisms: a review of the discriminative stimulus effects of benzodiazepines. Exp Clin Psychopharmacol 8:294–311

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Lutz B (2002) Molecular biology of cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids 66:123–142

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Masserano JM, Karoum F, Wyatt RJ (1999) SR 141716A, a cannabinoid receptor antagonist, potentiates the locomotor stimulant effects of amphetamine and apomorphine. Behav Pharmacol 10:429–432

    CAS  PubMed  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

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

    Article  CAS  PubMed  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1994) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    Article  Google Scholar 

  • Pertwee G (1999) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6:635–664

    PubMed  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

    PubMed  Google Scholar 

  • Quertemont E (2003) Discriminative stimulus effects of ethanol with a conditioned taste aversion procedure: lack of acetaldehyde substitution. Behav Pharmacol 14:343–350

    CAS  PubMed  Google Scholar 

  • Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand J-P, Soubrié P (2003) Anti-obesity effect of SR141716, a cannabinoid antagonist, in diet-induced obese mice. Am J Physiol Integr Comp Physiol 284:R345–R353

    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

    PubMed  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, Breliére JC, LeFur G (1998) SR 14528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther 284:644–650

    CAS  PubMed  Google Scholar 

  • Rowland NE, Mukherjee M, Robertson K (2001) Effects of the cannabinoid receptor antagonist SR 141716, alone and in combination with dexfenfluramine or naloxone, on food intake in rats. Psychopharmacology 159:111–116

    Google Scholar 

  • Rubino T, Patrini G, Massi P, Fuzio D, Vigano D, Giagnoni G, Parolaro D (1998) Cannabinoid-precipitated withdrawal: a time-course study of the behavioral aspect and its correlation with cannabinoid receptors and G protein expression. J Pharmacol Exp Ther 285:813–819

    CAS  PubMed  Google Scholar 

  • Santucci V, Storme JJ, Soubrié P, Le Fur G (1996) Arousal-enhancing properties of the CB1 cannabinoid receptor antagonist SR141716A in rats as assessed by electroencephalographic spectral and sleep-waking cycle analysis. Life Sci 58:PL103–PL110

    Article  CAS  PubMed  Google Scholar 

  • Schlicker E, Kathman M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572

    PubMed  Google Scholar 

  • Shannon HE, Holtzman SG (1976) Blockade of the discriminative effects of morphine in the rat by naltrexone and naloxone. Psychopharmacology 10:119–124

    Google Scholar 

  • Simiand J, Keane M, Keane PE, Soubrié P (1998) SR141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset. Behav Pharmacol 9:179–181

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA (2003) Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared with lean Zucker rats. Psychopharmacology 167:103–111

    CAS  PubMed  Google Scholar 

  • Weissman A (1978) Generalization of the discriminative stimulus properties of Δ9-tetrahydrocannabinol to cannabinoids with therapeutic potential. In: Colpaert FC, Rosecrans JA (eds) Stimulus properties of drugs: ten years of progress. Elsevier/North-Holland Biomedical, Amsterdam, pp 99–122

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

    CAS  PubMed  Google Scholar 

  • Wiley JL, Huffman JW, Balster RL, Martin BR (1995a) Pharmacological specificity of the discriminative stimulus effects of Δ9-tetrahydrocannabinol in rhesus monkeys. Drug Alcohol Depend 40:81–86

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the National Institute on Drug Abuse (NIDA), Bethesda, Md., USA, for supplies of Δ9-THC and SR-141716 as well as morphine. We thank Drs. A. Hiltunen and A. Karpinsky for their help with the statistical analysis. Preliminary results of this investigation were presented at the College on Problems of Drug Dependence (CPDD) 65th Annual Scientific Meeting, Bal Harbour (Miami), Fla., USA, June 14–19, 2003. The study was supported by NIDA grants DA 09064, 00253, and 13429 (Philadelphia, Pa., USA), 03801, 9158, 7215, and 00493 (Storrs, Conn., USA).

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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 & Michele Y. Harris

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

    Chen Li, Qian Liu & Alexandros Makriyannis

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  1. Torbjörn U. C. Järbe
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  2. Michele Y. Harris
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  3. Chen Li
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Correspondence to Torbjörn U. C. Järbe.

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Järbe, T.U.C., Harris, M.Y., Li, C. et al. Discriminative stimulus effects in rats of SR-141716 (rimonabant), a cannabinoid CB1 receptor antagonist. Psychopharmacology 177, 35–45 (2004). https://doi.org/10.1007/s00213-004-1916-5

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