Cortico-limbic circuitry for conditioned nicotine-seeking behavior in rats involves endocannabinoid signaling

Abstract

The endocannabinoid system plays an important role in conditioned drug seeking, but the neuronal mechanisms involved in this behavior are unclear. Here, we evaluate the role of endogenous cannabinoids in the cortico-limbic circuitry in cue-induced nicotine-seeking behavior in rats. Animals were first trained to self-administer nicotine (0.03 mg/kg/injection, IV) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and audiovisual stimuli. During subsequent sessions, nicotine was withdrawn and responding was reinforced by contingent presentation of the stimuli only. One month after nicotine removal, the cannabinoid CB1 receptor antagonist, rimonabant, was injected bilaterally into the shell of the nucleus accumbens (ShNAcc, 0.3, 3, or 30 ng/0.5 microl), the basolateral amygdala (BLA, 30 ng/0.5 microl), or the prelimbic cortex (PLCx, 30 ng/0.5 microl). Rimonabant injected into the ShNAcc dose-dependently reduced nicotine-seeking behavior without modifying spontaneous locomotor activity. Similar results were obtained when the drug (30 ng) was injected into the BLA or the PLCx. The anatomical specificity was confirmed in a control experiment using [(3)H]rimonabant. Fifteen minutes after drug injection, when the behavioral effects of rimonabant were already achieved, radioactivity was detected at the site of injection and had not diffused to adjacent regions. These findings demonstrate that increased endocannabinoid transmission critically triggers conditioned nicotine-seeking behavior in key cortico-limbic regions.