Cannabinoid Agonists but not Inhibitors of Endogenous Cannabinoid Transport or Metabolism Enhance the Reinforcing Efficacy of Heroin in Rats

Abstract

Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB 1 receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide. The natural cannnabinoid CB 1 receptor agonist delta-9-tetrahydrocannabinol (THC, 0.3-3 mg/kg i.p.) did not alter self-administration of heroin under a fixed-ratio one (FR1) schedule, except at a high 3 mg/kg dose which decreased heroin self-administration. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of 50 mg/kg heroin injections self-administered per session and the maximal ratio completed (break-point), with peak increases at 1 mg/kg THC. In addition, 1 mg/kg THC increased break-points and injections self-administered over a wide range of heroin injection doses (25À100 mg/kg), indicating an increase in heroin's reinforcing efficacy and not its potency. The synthetic cannabinoid CB 1 receptor agonist WIN55,212-2 (0.3-3 mg/kg i.p.) had effects similar to THC under the progressive-ratio schedule. In contrast, AM-404 (1-10 mg/ kg i.p.), an inhibitor of transport of anandamide, and URB-597 (0.01-0.3 mg/kg i.p.), an inhibitor of the enzyme fatty acid amide hydrolase (FAAH) that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB 1 receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB 1 receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids.

Endocannabinoid system involvement in brain reward processes related to drug abuse

“…The involvement of the endogenous cannabinoid system in the reinforcing effects of opioids is further supported by the findings that administration of CB1 agonists dramatically increases the motivation for self-administering heroin under a progressive-ratio schedule (137). In that study, however, administration of compounds that should increase endogenous cannabinoid system activity by interfering with the inactivation of endocannabinoids, such as the FAAH inhibitor URB-597 or the endocannabinoid transport inhibitor AM-404, did not increase selfadministration of heroin and, instead, at high doses decreased it (137).…”

“…In that study, however, administration of compounds that should increase endogenous cannabinoid system activity by interfering with the inactivation of endocannabinoids, such as the FAAH inhibitor URB-597 or the endocannabinoid transport inhibitor AM-404, did not increase selfadministration of heroin and, instead, at high doses decreased it (137). These results do not provide support for the hypothesis that opioid-induced release of endocannabinoids is a major mechanism underlying the influences of cannabinoids on opioid reinforcement and suggest, instead, that interactions at other levels may be responsible for these effects.…”

“…A commonly used preclinical model of relapse is reinstatement of extinguished intravenous drug self-administration by a priming injection of drug or by drug-associated stimuli (188)(189)(190). In a typical version of this procedure (137), animals learn to intravenously self-administer a drug over repeated daily sessions and then extinction sessions are conducted when responding has no programmed consequences (injections and, in some instances, drug-associated stimuli are not presented) until the animal's responding drops to a low, arbitrary level; reinstatement of operant drug-seeking behavior can then be tested by injecting a drug (drug-induced), by presenting visual or auditory stimuli previously associated with the drug (cue-induced) or by exposing animals to acute stress (stress induced).…”

Previous Exposure to THC Alters the Reinforcing Efficacy and Anxiety-Related Effects of Cocaine in Rats

“…A number of previous studies have demonstrated that cannabinoid ligands can modulate the reinforcing effects (Caille and Parsons, 2003;DeVries et al, 2003;Navarro et al, 2001;Norwood et al, 2003;Solinas et al, 2003Solinas et al, , 2005 and locomotor effects (Cadoni et al, 2001;Lamarque et al, 2001;Pontieri et al, 2001;Rubino et al, 2003) of opioid agonists. In the case of psychomotor stimulants, there is some evidence that exposure to THC or cannabinoid agonists may lead to behavioral sensitization with amphetamine (Gorriti et al, 1999;Lamarque et al, 2001).…”

Histamine in the brain: Beyond sleep and memory

“…Relevant to our study is that our results are in agreement with in vivo studies demonstrating that the administration of AM404 or URB597, an inhibitor of the metabolic pathway of the endocannabinoid anandamide, do not mimic the full spectrum of pharmacological responses produced by classical CB1 receptor agonists (see Refs. [45,46] for a review). Hence, understanding in what circumstances endocannabinoids are released and activate histaminergic cells warrants further investigations and may provide interesting hints to develop new therapeutic strategies in the treatment, for instance, of food intake disorders.…”