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

ABSTRACT:

Background and purpose

Opioids and cannabinoids interact in drug addiction and relapse. We investigated the effect of the opioid receptor antagonist naloxone and/or the cannabinoid CB(1) receptor antagonist rimonabant on cannabinoid-induced reinstatement of heroin seeking and on cannabinoid substitution in heroin-abstinent rats. EXPERIMENTAL APPROACH Rats were trained to self-administer heroin (30 µg·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(-1)) and rimonabant (0.3-3 mg·kg(-1)) on the reinstatement of heroin seeking induced by priming with the CB(1) receptor agonist WIN55,212-2 (WIN, 0.15-0.3 mg·kg(-1)). Then, in a parallel set of heroin-trained rats, we evaluated whether WIN (12.5 µg·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 results

Cannabinoid-induced reinstatement of heroin seeking was significantly attenuated by naloxone (1 mg·kg(-1)) and rimonabant (3 mg·kg(-1)) 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(-1)) and decreased by rimonabant (3 mg·kg(-1)).

Conclusions and implications

Our 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.

SUBMITTER: Fattore L

PROVIDER: S-EPMC3165962 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Opioid dependence is a major health concern across the world and does also occur in adolescents. While opioid substitution treatment (OST) has been thoroughly evaluated in adult populations, very few studies have examined its use in adolescents. There are concerns that OST is underutilised in adolescents with heroin dependence. We sought to measure changes in drug use among adolescents receiving OST and also to examine treatment attrition during the first 12 months of this treatment. METHODS:We included all heroin dependent patients aged under 18.5 years commencing OST at one outpatient multidisciplinary adolescent addiction treatment service in Dublin, Ireland. Psycho-social needs were also addressed during treatment. Drug use was monitored by twice weekly urine drugs screens (UDS). Change in the proportion of UDS negative for heroin was examined using the Wilcoxon signed rank test. Attrition was explored via a Cox Regression multivariate analysis. RESULTS:OST was commenced by 120 patients (51% female and mean age 17.3 years). Among the 39 patients who persisted with OST until month 12, heroin abstinence was 21% (95% confidence interval [CI]?=?9-36%) at month three and it was 46% (95% CI?=?30-63%) at month 12. Heroin use declined significantly from baseline to month three (p?<?0.001) and from month three to month 12 (p?=?0.01). Use of other drugs did not change significantly. People using cocaine during month 12 were more likely to be also using heroin (p?=?0.02). Unplanned exit occurred in 25% patients by 120 days. The independent predictors of attrition were having children, single parent family of origin, not being in an intimate relationship with another heroin user and evidence of cocaine use just before treatment entry. CONCLUSIONS:We found that heroin dependent adolescent patients achieved significant reductions in heroin use within three months of starting OST and this improved further after a year of treatment, about half being heroin abstinent at that stage. Patient drop out from treatment remains a challenge, as it is in adults. Cocaine use before and during treatment may be a negative prognostic factor.