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Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats

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Abstract

Rationale

Recently, we provided evidence for a cannabinoid mechanism in relapse to cocaine seeking in rats. There is also increasing evidence for functional cross-talk between cannabinoid and opioid systems in several physiological processes.

Objectives

This study was designed to evaluate whether the cannabinoid system plays a role in mediating the reinforcing and motivational effects of heroin and heroin-paired stimuli.

Methods

Male Wistar rats were trained to self-administer heroin (50 μg/kg per infusion) on fixed (FR5) or progressive ratio schedules of reinforcement in the presence of a discriminative and discrete heroin-associated cue. The selective cannabinoid CB1 antagonist SR141716A was given 30 min before the session to determine its effect on responding for heroin. Separate groups of rats were subjected to extinction training during which heroin-associated cues were absent and no heroin was delivered. During subsequent reinstatement tests, the effects of the cannabinoid agonist HU210 and the antagonist SR141716A on reinstatement of heroin seeking were evaluated.

Results

The cannabinoid antagonist dose-dependently reduced responding for heroin on the FR5 schedule and to a greater extent on the progressive ratio schedule. HU210 (20 μg/kg) reinstated heroin seeking behaviour following a 2-week extinction period, whereas SR141716A dose-dependently attenuated heroin seeking that was provoked by a priming injection of heroin (0.25 mg/kg) and heroin seeking that was triggered by re-exposure to heroin paired stimuli.

Conclusions

The results show that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors. Therefore, the present study provides a rationale for the use of cannabinoid antagonists in the treatment of opiate addiction.

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References

  • Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58:315–348

    Article  CAS  PubMed  Google Scholar 

  • Chaperon F, Thiebot MH (1999) Behavioral effects of cannabinoid agents in animals. Crit Rev Neurobiol 13:243–281

    Article  CAS  Google Scholar 

  • Chen J, Paredes W, Lowinson JH, Gardner EL (1990) Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex. Eur J Pharmacol 190:259–262

    Article  CAS  PubMed  Google Scholar 

  • De Vries TJ, Shippenberg TS (2002) Neural systems underlying opiate addiction. J Neurosci 22:3321–3325

    Google Scholar 

  • De Vries TJ, Schoffelmeer ANM, Binnekade R, Vanderschuren LJMJ (1999) Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration. Psychopharmacology 143:254–260

    Article  Google Scholar 

  • De Vries TJ, Shaham Y, Homberg JR, Crombag H, Schuurman K, Dieben J, Vanderschuren LJMJ, Schoffelmeer ANM (2001) A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 7:1151–1154

    Article  Google Scholar 

  • Einhorn LC, Johansen PA, White FJ (1988) Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area. J Neurosci 8:100–112

    CAS  PubMed  Google Scholar 

  • Ettenberg A, Pettit HO, Bloom FE, Koob GF (1982) Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology 78:204–209

    Article  CAS  PubMed  Google Scholar 

  • Fuchs RA, See RE (2002) Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology 160:425–433

    Article  CAS  PubMed  Google Scholar 

  • Gardner EL, Vorel SR (1998) Cannabinoid transmission and reward-related events. Neurobiol Dis 5:502–533

    Article  CAS  PubMed  Google Scholar 

  • Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2:358–363

    Article  CAS  PubMed  Google Scholar 

  • Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Izzo E, Orsini C, Koob GF, Pulvirenti L (2001) A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule. Pharmacol Biochem Behav 68:701–708

    Article  CAS  PubMed  Google Scholar 

  • Johnson LR, Aylward RL, Hussain Z, Totterdell S (1994) Input from the amygdala to the rat nucleus accumbens: its relationship with tyrosine hydroxylase immunoreactivity and identified neurons. Neuroscience 61:851–865

    Article  CAS  PubMed  Google Scholar 

  • Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558

    CAS  PubMed  Google Scholar 

  • Manzanares J, Corchero J, Romero J, Fernandez–Ruiz JJ, Ramos JA, Fuentes JA (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci 20:287–294

    Article  CAS  PubMed  Google Scholar 

  • Manzoni OJ, Bockaert J (2001) Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens. Eur J Pharmacol 412: R3–R5

    Article  CAS  PubMed  Google Scholar 

  • Mascia MS, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A, Fratta W (1999) Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB1 receptor knockout mice. Eur J Pharmacol 383: R1–R2

    Article  CAS  PubMed  Google Scholar 

  • McFarland K, Ettenberg A (1997) Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli. Psychopharmacology 131:86–92

    Article  CAS  PubMed  Google Scholar 

  • Navarro M, Chowen J, Carrera MA, del Arco I, Villanua MA, Martin Y, Roberts AJ, Koob GF, Rodriquez de Fonseca F (1998) CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine–dependent rats. Neuroreport 9:3397–3402

    Article  CAS  PubMed  Google Scholar 

  • Navarro M, Carrera MR, Fratta W, Valverde O, Cossu G, Fattore L, Chowen JA, Gomez R, del Arco, I, Villanua MA, Maldonado R, Koob GF, Rodriquez de Fonseca F (2001) Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 21:5344–5350

    CAS  PubMed  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Meth 66:1–11

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Rubino T, Massi P, Vigano D, Fuzio D, Parolaro D (2000) Long-term treatment with SR141716A, the CB1 receptor antagonist, influences morphine withdrawal syndrome. Life Sci 66:2213–2219

    Article  CAS  PubMed  Google Scholar 

  • Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42

    Article  CAS  PubMed  Google Scholar 

  • Stewart J (1984) Reinstatement of heroin and cocaine self-administration behavior in the rat by intracerebral application of morphine in the ventral tegmental area. Pharmacol Biochem Behav 20:917–923

    Article  CAS  PubMed  Google Scholar 

  • Stewart J, Vezina P (1988) A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior. Brain Res 457:287–294

    Article  CAS  PubMed  Google Scholar 

  • Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu-1 opioid receptor mechanism. Science 276:2048–2050

    Article  CAS  PubMed  Google Scholar 

Download references

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Correspondence to Taco J. De Vries.

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De Vries, T.J., Homberg, J.R., Binnekade, R. et al. Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology 168, 164–169 (2003). https://doi.org/10.1007/s00213-003-1422-1

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  • DOI: https://doi.org/10.1007/s00213-003-1422-1

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