Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

Abstract

Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drugseeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drugseeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB 1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotine-related stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/ injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After self-administration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to lever-press for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence.

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

“…In answer to this question a sizeable literature suggests that smoking is maintained by both the primary reinforcing properties of nicotine and its related ability to establish associated environmental stimuli as conditioned stimuli, which can subsequently induce craving and provoke drug-seeking (Rose and Levin 1991;Perkins 1999;Caggiula et al 2001;Cohen et al 2005). Research by our laboratory concurs fully with this hypothesis, but extends it to include a distinct behavioral property of nicotine -its capacity to enhance responding for an already reinforcing non-nicotine stimulus Chaudhri et al in press).…”

Role of the cannabinoid system in the effects induced by nicotine on anxiety-like behaviour in mice

“…Previous studies have also reported that rimonabant blocks the reinforcing effects of nicotine (Cohen et al, 2002) and avoids reinstatement of nicotine seeking in rats (Cohen et al, 2005).…”

Investigation of endocannabinoid modulation of conditioned responding evoked by a nicotine CS and the Pavlovian stimulus effects of CP 55,940 in adult male rats

“…Briefly, rimonabant has been found to decrease nicotine self-administration (Cohen et al 2002;Kodas et al 2007), cue-induced reinstatement of nicotine seeking (Cohen et al 2004;De Vries et al 2005), and nicotine-conditioned place preferences (Forget et al 2005;Le Foll and Goldberg 2004). The operant discriminative stimulus (S D ) effects of nicotine do not appear to be affected by pretreatment with rimonabant (Cohen et al 2002;Le Foll and Goldberg 2004;Zaniewska et al 2006).…”