Cannabinoid mechanism in reinstatement of heroin‐seeking after a long period of abstinence in rats

Abstract

Because opioid and cannabinoid systems have been reported to interact in the modulation of addictive behaviour, this study was aimed at investigating the ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a prolonged period of extinction. In rats previously trained to self-administer heroin intravenously, non-contingent non-reinforced priming administrations of heroin and cannabinoids were presented after long-term extinction, and lever pressing following injections was observed. Results showed that: (i) intravenous priming infusions of heroin (0.1 and 0.2 mg/kg) lead to reinstatement of drug-seeking behaviour; (ii) intraperitoneal priming injections of the central cannabinoid receptor agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazinyl) (1-naphthalenyl)methanonemesylate (WIN 55,212-2, 0.15 and 0.3 mg/kg) and (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940, 0.05 and 0.1 mg/kg), but not delta9-tetrahydrocannabinol (delta9-THC, 0.1-1.0 mg/kg), effectively restored heroin-seeking behaviour; (iii) intraperitoneal priming injection of the central cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 0.3 mg/kg) did not reinstate responding, but (iv) completely prevented heroin-induced reinstatement of drug-seeking behaviour. Moreover, heroin-seeking behaviour was still present for a few days following cannabinoid primings, indicating a long-lasting effect of cannabinoids on responding for heroin. These findings indicate that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that SR 141716A prevents drug-seeking behaviour, suggesting that the use of the cannabinoid antagonist could have some therapeutic benefits in heroin-induced relapse.

Heroin-Induced Reinstatement is Specific to Compulsive Heroin Use and Dissociable from Heroin Reward and Sensitization

“…This apparent discrepancy may result from a combination of different procedural factors. First, in previous studies, daily access time to heroin was longer than the minimum of the present study (ie, 1 h) and ranged between 2 and 12 h, with 3 h being the most frequent duration of access (eg, de Wit and Stewart, 1981;Stewart and Wise, 1992;Shaham and Stewart, 1995;De Vries et al, 1998;Fuchs and See, 2002;Fattore et al, 2003;Leri et al, 2004;Luo et al, 2004;Yao et al, 2005). Thus, together with the present findings, this difference may point to the existence of some threshold duration below which most individuals readily learn to take heroin without becoming responsive to its priming effects and above which they begin to respond to these effects.…”

“…Thus, together with the present findings, this difference may point to the existence of some threshold duration below which most individuals readily learn to take heroin without becoming responsive to its priming effects and above which they begin to respond to these effects. Second, in most, except a few, previous studies, responding during reinstatement testing was followed by discrete stimuli that were originally paired with heroin injections (eg, de Wit and Stewart, 1981;Stewart and Wise, 1992;Shaham and Stewart, 1995;Fattore et al, 2003;Leri et al, 2004;Luo et al, 2004;Yao et al, 2005) whereas in the present study, no programmed responsecontingent cues were available during reinstatement testing. As drugs of abuse can dramatically increase responding for both unconditioned and conditioned sensory stimuli in drug-naïve animals (eg, Berlyne, 1969;Gomer and Jakubczak, 1974;Robbins, 1976;Robbins and Koob, 1978), this factor could also have contributed to the specific outcome of the present study.…”

The Roman High- and Low-Avoidance Rat Lines Differ in the Acquisition, Maintenance, Extinction, and Reinstatement of Intravenous Cocaine Self-Administration

“…To this aim, the acquisition, maintenance and extinction of cocaine self-administration (SA) behavior was assessed in RHA and RLA rats using a continuous (FR-1) reinforcement schedule with lever-pressing as operandum. Next, the propensity of RHA and RLA rats, kept under extinction conditions for 3 weeks, to resume lever-pressing behavior upon the administration of priming doses of cocaine was investigated by means of a between-session model of extinction/reinstatement, as previously described (Fattore et al, 2003). Finally, cocaine was made again contingently available to compare the ability of the two lines to reacquire SA behavior.…”

Positron Emission Tomography Molecular Imaging of Dopaminergic System in Drug Addiction

“…Laboratory animal study has shown that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors (De Vries et al, 2003).Drugs antagonizing the cannabinoid receptors to modulate DA cells but also postsynaptic responses from DA stimulation (Wallmichrath and Szabo, 2002;Julian et al, 2003) have shown promising results in attenuating the reinforcing effects of various types of drugs of abuse in laboratory animals (De Vries et al, 2001). As far as heroin is concerned, there are findings indicating that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that cannabinoid antagonist can prevent drug-seeking behaviors (Fattore et al, 2003).…”