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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58:315–348
Chaperon F, Thiebot MH (1999) Behavioral effects of cannabinoid agents in animals. Crit Rev Neurobiol 13:243–281
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
De Vries TJ, Shippenberg TS (2002) Neural systems underlying opiate addiction. J Neurosci 22:3321–3325
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
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
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
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
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
Gardner EL, Vorel SR (1998) Cannabinoid transmission and reward-related events. Neurobiol Dis 5:502–533
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
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
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
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
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
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
Manzoni OJ, Bockaert J (2001) Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens. Eur J Pharmacol 412: R3–R5
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
McFarland K, Ettenberg A (1997) Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli. Psychopharmacology 131:86–92
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
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
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
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
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
Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42
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
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
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
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-003-1422-1