Cannabinoid Modulation of the Reinforcing and Motivational Properties of Heroin and Heroin-associated Cues in Rats

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2003 Apr 2

PMID 12669182

Citations 70

Authors

Taco J de Vries

Judith R Homberg

Rob Binnekade

Halfdan Raaso

Anton N M Schoffelmeer

Affiliations

Soon will be listed here.

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 microg/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 microg/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.

Citing Articles

Involvement of CB1R and CB2R Ligands in Sleep Disorders and Addictive Behaviors in the Last 25 Years.

Perez-Morales M, Espinoza-Abad R, Garcia-Garcia F Pharmaceuticals (Basel). 2025; 18(2).

PMID: 40006078 PMC: 11860062. DOI: 10.3390/ph18020266.

Interfering with reconsolidation by rimonabant results in blockade of heroin-associated memory.

Lin J, Peng Y, Zhang J, Cheng J, Chen Q, Wang B Front Pharmacol. 2024; 15:1361838.

PMID: 38576487 PMC: 10991728. DOI: 10.3389/fphar.2024.1361838.

Dysregulation of the endogenous cannabinoid system following opioid exposure.

Mohammad Aghaei A, Saali A, Canas M, Weleff J, DSouza D, Angarita G Psychiatry Res. 2023; 330:115586.

PMID: 37931479 PMC: 10842415. DOI: 10.1016/j.psychres.2023.115586.

Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge.

Soler-Cedeno O, Xi Z Cells. 2022; 11(20).

PMID: 36291128 PMC: 9600259. DOI: 10.3390/cells11203262.

Therapeutic potential of PIMSR, a novel CB1 receptor neutral antagonist, for cocaine use disorder: evidence from preclinical research.

Galaj E, Hempel B, Moore A, Klein B, Bi G, Gardner E Transl Psychiatry. 2022; 12(1):286.

PMID: 35851573 PMC: 9293959. DOI: 10.1038/s41398-022-02059-w.

References

Herkenham M, Lynn A, Little M, Johnson M, Melvin L, De Costa B . Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990; 87(5):1932-6. PMC: 53598. DOI: 10.1073/pnas.87.5.1932. View

de Vries T, Schoffelmeer A, Binnekade R, Vanderschuren L . Dopaminergic mechanisms mediating the incentive to seek cocaine and heroin following long-term withdrawal of IV drug self-administration. Psychopharmacology (Berl). 1999; 143(3):254-60. DOI: 10.1007/s002130050944. View

Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S . SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994; 350(2-3):240-4. DOI: 10.1016/0014-5793(94)00773-x. View

Fuchs R, See R . Basolateral amygdala inactivation abolishes conditioned stimulus- and heroin-induced reinstatement of extinguished heroin-seeking behavior in rats. Psychopharmacology (Berl). 2002; 160(4):425-33. DOI: 10.1007/s00213-001-0997-7. View

Johnson L, Aylward R, Hussain Z, Totterdell S . Input from the amygdala to the rat nucleus accumbens: its relationship with tyrosine hydroxylase immunoreactivity and identified neurons. Neuroscience. 1994; 61(4):851-65. DOI: 10.1016/0306-4522(94)90408-1. View

Einhorn L, Johansen P, White F . Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area. J Neurosci. 1988; 8(1):100-12. PMC: 6569379. View

Giuffrida A, Parsons L, Kerr T, Rodriguez de Fonseca F, Navarro M, Piomelli D . Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci. 1999; 2(4):358-63. DOI: 10.1038/7268. View

Richardson N, Roberts D . Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods. 1996; 66(1):1-11. DOI: 10.1016/0165-0270(95)00153-0. View

de Vries T, Shippenberg T . Neural systems underlying opiate addiction. J Neurosci. 2002; 22(9):3321-5. PMC: 6758389. DOI: 20026357. View

10.

Stewart J, Vezina P . A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior. Brain Res. 1988; 457(2):287-94. DOI: 10.1016/0006-8993(88)90698-1. View

11.

Ameri A . The effects of cannabinoids on the brain. Prog Neurobiol. 1999; 58(4):315-48. DOI: 10.1016/s0301-0082(98)00087-2. View

12.

Stewart J . Reinstatement of heroin and cocaine self-administration behavior in the rat by intracerebral application of morphine in the ventral tegmental area. Pharmacol Biochem Behav. 1984; 20(6):917-23. DOI: 10.1016/0091-3057(84)90017-0. View

13.

Manzanares J, Corchero J, Romero J, Fernandez-Ruiz J, Ramos J, Fuentes J . Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci. 1999; 20(7):287-94. DOI: 10.1016/s0165-6147(99)01339-5. View

14.

Shalev U, Grimm J, Shaham Y . Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev. 2002; 54(1):1-42. DOI: 10.1124/pr.54.1.1. View

15.

Mascia M, Obinu M, Ledent C, Parmentier M, Bohme G, Imperato A . Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice. Eur J Pharmacol. 1999; 383(3):R1-2. DOI: 10.1016/s0014-2999(99)00656-1. View

16.

Rubino T, Massi P, Vigano D, Fuzio D, Parolaro D . Long-term treatment with SR141716A, the CB1 receptor antagonist, influences morphine withdrawal syndrome. Life Sci. 2000; 66(22):2213-9. DOI: 10.1016/s0024-3205(00)00547-6. View

17.

Chen J, PAREDES W, Lowinson J, Gardner E . Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex. Eur J Pharmacol. 1990; 190(1-2):259-62. DOI: 10.1016/0014-2999(90)94136-l. View

18.

Izzo E, Orsini C, Koob G, Pulvirenti L . A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule. Pharmacol Biochem Behav. 2001; 68(4):701-8. DOI: 10.1016/s0091-3057(01)00472-5. View

19.

McFarland K, Ettenberg A . Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli. Psychopharmacology (Berl). 1997; 131(1):86-92. DOI: 10.1007/s002130050269. View

20.

de Vries T, Shaham Y, Homberg J, CROMBAG H, Schuurman K, Dieben J . A cannabinoid mechanism in relapse to cocaine seeking. Nat Med. 2001; 7(10):1151-4. DOI: 10.1038/nm1001-1151. View