Differential effect of opioid and cannabinoid receptor blockade on heroin‐seeking reinstatement and cannabinoid substitution in heroin‐abstinent rats

Abstract

BACKGROUND AND PURPOSEOpioids and cannabinoids interact in drug addiction and relapse. We investigated the effect of the opioid receptor antagonist naloxone and/or the cannabinoid CB1 receptor antagonist rimonabant on cannabinoid-induced reinstatement of heroin seeking and on cannabinoid substitution in heroin-abstinent rats. EXPERIMENTAL APPROACHRats were trained to self-administer heroin (30 mg·kg -1 per infusion) under a fixed-ratio 1 reinforcement schedule. After extinction of self-administration (SA) behaviour, we confirmed the effect of naloxone (0.1-1 mg·kg ). Then, in a parallel set of heroin-trained rats, we evaluated whether WIN (12.5 mg·kg -1 per infusion) SA substituted for heroin SA after different periods of extinction. In groups of rats in which substitution occurred, we studied the effect of both antagonists on cannabinoid intake. KEY RESULTSCannabinoid-induced reinstatement of heroin seeking was significantly attenuated by naloxone (1 mg·kg ) and fully blocked by co-administration of sub-threshold doses of the two antagonists. Moreover, contrary to immediate (1 day) or delayed (90 days) drug substitution, rats readily self-administered WIN when access was given after 7, 14 or 21 days of extinction from heroin, and showed a response rate that was positively correlated with the extinction period. In these animals, cannabinoid intake was increased by naloxone (1 mg·kg CONCLUSIONS AND IMPLICATIONSOur findings extend previous research on the crosstalk between cannabinoid and opioid receptors in relapse mechanisms, which suggests a differential role in heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats.

Management of impulse control disorders in Parkinson's disease: Controversies and future approaches

“…One approach to identifying potential therapies for ICD in PD is by analogy to impulsivity and addiction not associated with PD, given the similarities in behavioral manifestations and anatomic substrates, although limitations are present in such extrapolations. For instance, non‐PD impulsivity or addiction studies in animals, and genetic studies, suggest involvement of mu opioid, cannabinoid, nicotinic, and D4 dopamine systems . Although recognizing that data on pre‐clinical efficacy obtained in models with an intact dopaminergic system may not be predictive of ICDs in PD patients who have dopaminergic systems affected by the disease process is important, these data identify potential therapeutic targets for PD ICDs.…”

Enkephalin levels and the number of neuropeptide Y-containing interneurons in the hippocampus are decreased in female cannabinoid-receptor 1 knock-out mice

“…CB1 receptor agonist-induced amnesic effects and memory consolidation are notably impaired by morphine activation of MORs, which are also the mediators of many of the central neural effects produced by enkephalin [10;48]. Moreover, cannabinoid abuse increases one's likelihood of developing opiate addiction and vice versa [11-13]. Prenatal and adolescent exposure to THC can also increase heroin-seeking tendencies in adults [9;38;41].…”

The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL‐α expression following short‐term morphine withdrawal

“…This is consistent with results from previous studies, which showed that morphine is effective at reactivating opiate‐seeking behaviour in mice and that the CPP paradigm is useful for investigating mechanisms underlying relapse of drug abuse (Martin et al ., ; Ribeiro Do Couto et al ., ). Interestingly, drug‐seeking behaviour associated with a variety of abused substances can be reinstated or attenuated following CB 1 receptor activation or antagonism respectively (De Vries et al ., ; Alvarez‐Jaimes et al ., ; Fattore et al ., ). However, how the eCB system affects drug‐related addiction behaviours was unclear.…”

“…It has been reported that mice lacking CB1 receptors (CB1 knockouts) fail to exhibit conditioned place preference (CPP) with morphine (Martin et al, 2000) and do not acquire morphine self-administration (Ledent et al, 1999;Cossu et al, 2001). In addition, activation of CB1 receptors has been shown to reinstate heroin-seeking behaviour (De Vries et al, 2003;Fattore et al, 2011), whereas blockade of CB1 receptors in a related region attenuates cue-induced heroin-seeking behaviour (Alvarez-Jaimes et al, 2008). However, how the eCB system affects drug-related addiction behaviours remains unclear.…”