The Cannabinoid CB1 Antagonist N-Piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide (SR-141716A) Differentially Alters the Reinforcing Effects of Heroin under Continuous Reinforcement, Fixed Ratio, and Progressive Ratio Schedules of Drug Self-Administration in Rats

Abstract

Activation or blockade of cannabinoid CB1 receptors markedly alters many effects of opioids. In the present study, we investigated whether the cannabinoid antagonist (N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR-141716A) could alter the reinforcing effects of heroin in rats. A ⌬ 9 -tetrahydrocannabinol (THC) drugdiscrimination procedure was first used to determine effective CB1 antagonist doses of SR-141716A and optimal pretreatment times for self-administration studies. Subsequently, Sprague-Dawley rats learned to self-administer heroin under three different schedules of intravenous drug injection: a continuous reinforcement schedule [fixed ratio (FR)1], a fiveresponse, fixed ratio schedule (FR5), and a progressive ratio schedule. Then, SR-141716A (1 mg/kg i.p.) was administered 60 min before the start of the session for three consecutive daily sessions. SR-141716A markedly decreased heroin selfadministration under the progressive ratio schedule at heroin doses ranging from 12.5 to 100 g/kg/injection. In contrast, SR-141716A had no effect on heroin self-administration under the FR1 schedule at heroin doses of 50 or 100 g/kg/injection, but produced small decreases in self-administration at lower doses (25 and 12.5 g/kg/injection). Consistent with a behavioral economics evaluation, SR-141716A produced a small but significant decrease in self-administration of the higher 50 g/ kg/injection dose of heroin when the fixed ratio requirement was raised to five (FR5). Thus, blockade of CB1 receptors differentially decreased the reinforcing efficacy of heroin depending on the number of responses required for each injection (price). These findings indicate a facilitatory modulation of opioid reward by endogenous cannabinoid activity and provide support for the use of cannabinoid CB1 antagonists as medications for heroin addiction.A wide range of functional interactions between opioid and cannabinoid systems have been found in the areas of nociception, physical dependence development, direct measures of reward, such as intravenous drug self-administration behavior, and indirect measures of reward, such as drug-induced alterations in thresholds for electrical brain self-stimulation and conditioned place preference (Manzanares et al., 1999;Maldonado, 2002). Interactions reported have largely involved opioid modulation of cannabinoid effects. For example, self-administration of cannabinoid CB1 receptor agonists is reduced by pretreatment with an opioid antagonist in mice and squirrel monkeys (Goldberg et al., 2001;Navarro et al., 2001). Also, development of a preference for a distinctive compartment associated with THC administration is lost in -receptor knockout mice (Ghozland et al., 2002), and reduction by THC of the threshold for electrical brain self-stimulation is prevented by naloxone administration (Gardner and Lowinson, 1991). Studies of cannabinoid effects on opioid reinforcement indicate that opioid-cannabinoid interactions can also be bidirectional. For example...

Adolescent Cannabis Exposure Alters Opiate Intake and Opioid Limbic Neuronal Populations in Adult Rats

“…The correlation between the CB 1 receptor and heroin self-administration underscores the significant functional interactions between the cannabinoid and opioid systems. In line with previous studies, we also confirmed an acute pharmacological regulation of cannabinoid receptor modulation of opiate self-administration behavior (Caille and Parsons, 2003;Navarro et al, 2001;Solinas et al, 2003). Blockade of the CB 1 receptor with Rimonabant (at the 3 mg/ kg dose) inhibited heroin consumption, but there was no altered sensitivity in the THC-exposed rats, perhaps reflective of the lack of CB 1 receptor alterations.…”

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

“…One day after the last THC or vehicle injection, rats in Experiment 1 were implanted with catheters in the right jugular vein under aseptic conditions using i.p. ketamine (60 mg/kg) and xylazine (10 mg/kg) anesthesia as previously described (Solinas et al, 2003). When rats developed a blocked catheter in an advanced phase of the experiment, a second catheter was implanted in the left jugular vein.…”

“…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).…”

Blockade of THC-Seeking Behavior and Relapse in Monkeys by the Cannabinoid CB1-Receptor Antagonist Rimonabant

“…This system appears to be capable of modulating the rewarding effects of many drugs of abuse, including opioids (De Vries et al, 2003;Navarro et al, 2001;Solinas et al, 2003), nicotine (Cohen et al, 2002;Le Foll and Goldberg, 2005), and alcohol (De Vries and Schoffelmeer, 2005;Economidou et al, 2006). Ironically, little attention has been focused on potential pharmacotherapies specifically targeting the substantial and growing problem of cannabis use disorders (Compton et al, 2004).…”