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

Abstract

Accumulating evidence suggests the endocannabinoid system modulates environmental cues' ability to induce seeking of drugs, including nicotine and alcohol. However, little attention has been directed toward extending these advances to the growing problem of cannabis use disorders. Therefore, we studied intravenous self-administration of D 9 -tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, using a second-order schedule of drug seeking. Squirrel monkeys' lever responses produced only a brief cue light until the end of the session, when the final response delivered THC along with the cue. When a reinstatement procedure was used to model relapse following a period of abstinence, THC-seeking behavior was robustly reinstated by the cue or by pre-session administration of THC, other cannabinoid agonists, or morphine, but not cocaine. The cannabinoid antagonist rimonabant blocked cueinduced drug seeking, THC-induced drug seeking, and the direct reinforcing effects of THC. Thus, rimonabant and related medications might be effective as treatments for cannabinoid dependence.

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

“…Conversely, CB1 agonists reinstate extinguished drug-seeking behaviour (which is equivalent of relapse in humans) for cannabinoids [100,101], opioids [102,103], ethanol [104,105] and nicotine [106]. In humans, relapse is a major problem in the treatment of addiction, and relapse prevention is the main goal to achieve in addicts.…”

A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking

“…A current theory holds that endocannabinoids decrease drug-seeking behavior, in part, by diminishing the secondary/environmental influences of drugs on motivated behavior (Le Foll and Goldberg 2004;Vries and Schoffelmeer 2005). For example, when responding is maintained by drug-associated environmental cues under second-order schedules of reinforcement, rimonabant significantly decreases drug seeking (Justinova et al 2008). Furthermore, endocannabinoid disruption is particularly effective at reducing cue-induced reinstatement, a model of relapse in humans that incorporates the influence of conditioned environmental stimuli on reward seeking (Epstein et al 2006).…”

“…Furthermore, endocannabinoid disruption is particularly effective at reducing cue-induced reinstatement, a model of relapse in humans that incorporates the influence of conditioned environmental stimuli on reward seeking (Epstein et al 2006). Indeed, rimonabant decreases the propensity for conditioned cues to reinstate responding for various drugs of abuse (Vries and Schoffelmeer 2005;Justinova et al 2008). To assess whether disrupting endocannabinoid signaling decreases cue-evoked dopamine signaling, Cheer and colleagues (Oleson et al 2012) treated rats with rimonabant while responding was maintained by brain stimulation reward in a cued intracranial self-stimulation task.…”

Effects of Alterations in Cannabinoid Signaling, Alone and in Combination with Morphine, on Pain-Elicited and Pain-Suppressed Behavior in Mice

“…Agonists at cannabinoid type 1 (CB1) receptors produce behavioral effects that include disruption of locomotor activity (Pascual et al, 2005;Smith et al, 2009), dysregulation of food consumption (Jä rbe and DiPatrizio, 2005;Li et al, 2006), interference with thermoregulation (Wang et al, 2008;Diaz et al, 2009), and reinforcing effects (Justinova et al, 2008;Negus and Rice, 2009). Research also implicates the endogenous cannabinoid system in the mediation of pain responses.…”