Blockade by the Cannabinoid CB1 Receptor Antagonist, Rimonabant (SR141716), of the Potentiation by Quinelorane of Food-Primed Reinstatement of Food-Seeking Behavior

Abstract

It has been shown previously that the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716), reduced the intake of palatable food as well as the self-administration of several drugs of abuse, suggesting that endocannabinoid systems play a role in brain reward function. The present study investigated whether a cannabinoid step was involved in food-seeking behavior induced by explicit stimuli, using an operant reinstatement procedure in rats. Experimental sessions consisted of a 15-min food rewarded period, followed by a 45-min extinction period. Rimonabant did not affect the response reinstatement induced by noncontingent delivery of food pellets, but prevented (0.03-0.3 mg/kg) the potentiation by quinelorane, a dopamine D3 receptor-preferring agonist, of food-seeking behavior. A possible link between cannabinoid processes and D3-and/or D2-mediated dopaminergic transmission was further investigated by studying Fos protein expression in cortico-limbic structures in D3 (D3À/À) and D2 (D2À/À) knockout mice. Rimonabant (10 mg/kg) increased Fos immunoreactivity in the prefrontal cortex (pFCortex) and in the shell but not the core of the nucleus accumbens (NAcc). Fos induction by this dose of rimonabant was not seen in mice lacking CB1 receptors, providing clear evidence for the involvement of CB1 receptors. In the NAcc shell, the effect of rimonabant was suppressed in D3À/À, but remained unchanged in D2À/À mice. In contrast, Fos expression by rimonabant in the pFCortex was impervious to D2 or D3 receptor deletion. In conclusion, these data indicate first that rimonabant prevented the enhancement by quinelorane of the appetitive value of food pellets unexpectedly delivered during extinction and second that rimonabant effects might involve D3 receptor-mediated processes. Overall, these results are consistent with the notion that endocannabinoid functions control brain reward processes and in particular the capacity of explicit stimuli to precipitate food-seeking behavior.

Synergistic Interactions between Cannabinoids and Environmental Stress in the Activation of the Central Amygdala

“…SR141716 produced a dose-dependent increase in Fos expression within the BLA and CeA, suggesting that eCB tone suppresses amygdala activity, an effect observed within other limbic regions such as the prefrontal cortex and nucleus accumbens (Alonso et al, 1999;Duarte et al, 2004).…”

Cannabinoid CB1 Receptor Antagonists as Promising New Medications for Drug Dependence

“…Some effects of SR141716 are diminished in dopamine D 3 receptor-deficient mice (Duarte et al, 2003), suggesting that dopamine D 3 receptors are involved in CB 1 receptor-mediated processes. Since dopamine D 3 receptors and cannabinoid CB 1 receptors are both expressed in the mesolimbic dopamine brain reward circuit (Mailleux and Vanderhaeghen, 1992;Diaz et al, 2000;Le Foll et al, 2002, 2003a, these two types of receptors may control the dopamine-releasing effect of drug-associated cues.…”

“…Furthermore, blockade of cannabinoid CB 1 receptors by SR141716 prevents the development of food-induced CPP (Chaperon et al, 1998). Nevertheless, the neurobiological mechanisms underlying these effects are still unclear and may also involve dopaminergic transmission (Duarte et al, 2003). Further work is needed to determine whether similar or different neurotransmitter systems are involved in the effects of cannabinoid CB 1 receptor blockade on appetite and drug-seeking behavior.…”

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

“…Given the findings that rimonabant reduced responding for nicotineassociated cues, even after several months of nicotine abstinence, and antagonizes dopamine release caused by nicotine addiction, it is reasonable that the CB1 receptor antagonist can reduce both nicotine-seeking behavior and nicotine-reinforcing effects, probably by preventing nicotine-induced dopamine (DA) release in limbic dopaminergic areas during self-administration (Cohen et al, 2002(Cohen et al, , 2005. The action of rimonabant on both reducing nicotine craving and weight gain may be, at least in part, the result of a common mechanism involving a dopamine receptor-mediated process (Duarte et al, 2004). In this respect, studies of rimonabant treatment on conditioned response for nicotine-and sucroseassociated cues in a long-term extinction-reinstatement animal model demonstrated a strongly decrease cue-induced reinstatement of nicotine-and sucrose-seeking behavior .…”