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


OBJECTIVE
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.
De Vries
Taco J
TJ
Research Institute Neurosciences Vrije Universiteit, Drug Abuse Program, Department of Medical Pharmacology, VU Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands. tj.de_vries.pharm@med.vu.nl.
Homberg
Judith R
JR
Research Institute Neurosciences Vrije Universiteit, Drug Abuse Program, Department of Medical Pharmacology, VU Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
Binnekade
Rob
R
Research Institute Neurosciences Vrije Universiteit, Drug Abuse Program, Department of Medical Pharmacology, VU Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
Raasø
Halfdan
H
Research Institute Neurosciences Vrije Universiteit, Drug Abuse Program, Department of Medical Pharmacology, VU Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
Schoffelmeer
Anton N M
ANM
Research Institute Neurosciences Vrije Universiteit, Drug Abuse Program, Department of Medical Pharmacology, VU Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced / Q000517:prevention & control; D002186:Cannabinoids / Q000494:pharmacology*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D003932:Heroin / Q000008:administration & dosage*; D008297:Male; D009042:Motivation; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D012054:Reinforcement, Psychology; D012646:Self Administration
D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D003932:Heroin