Role of the kappa-opioid receptor system in stress-induced reinstatement of nicotine seeking in rats

Abstract

Rationale: The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest that the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa-opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future.

Objectives: We sought to determine whether there was a stress-specific role of the kappa-opioid system in nicotine seeking behavior.

Method: Groups of male Long Evans rats were trained to self-administer nicotine intravenously; their operant responding for nicotine was extinguished prior to tests of reinstatement. Pretreatment with systemic injections of the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was given prior to tests of stress (systemic injections of yohimbine (YOH)) or cue-induced reinstatement of nicotine seeking. Systemic injections of the KOR agonist U50,488 were also given in a test for reinstatement of nicotine seeking.

Results: Nor-BNI pretreatment at 1h and 24h prior to testing was able to block YOH-induced, but not cue-induced reinstatement of nicotine seeking. U50,488 reinstated nicotine seeking behavior in a dose-dependent manner.

Conclusions: These findings support the hypothesis that the kappa-opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.

Keywords: Nicotine; Nor-binaltorphimine; Reinstatement; Stress; U50,488; Yohimbine.

Fig. 1. Yohimbine-Induced Reinstatement Attenuated by KOR Antagonism

A) Mean (+/− SEM) number of responses made on the last two days of extinction and on the day of the YOH reinstatement test by each group: VEH1hrYOH (n=7), NB1hrYOH (n=8), and NB24hrYOH (n=9). YOH significantly reinstated nicotine seeking in rats given vehicle pretreatment. This was attenuated in animals pretreated with nor-BNI, 1 hr and 24 hrs prior to testing. * Significant difference between extinction session and the test for reinstatement in the VEH1hrYOH group. + Significant difference between the VEH1hrYOH group and NB1hrYOH or NB24hrYOH groups during the test for reinstatement.

Fig. 2. Effect of nor-BNI pretreatment (1hr) on Extinction Responding

Mean (+/− SEM) numbers of active and inactive lever responses made during extinction (the day prior to the reinstatement test) 1 hr following an injection of nor-BNI (n=9). There were no significant effects.

Fig. 3. KOR Activation Reinstates Nicotine Seeking

Mean (+/− SEM) numbers of active and inactive lever responses made during reinstatement test in which rats received 4 different doses of U50,488 in counterbalanced order. N=15. U50, 488 significantly reinstated nicotine seeking when given at 2.5 and 5mg/kg. * = Significant difference from vehicle on active lever responses.

Fig. 4. Cue-Induced Reinstatement is not Affected by KOR Antagonism

A) Mean (+/− SEM) number of active lever responses made on the last two days of extinction and on the day of the cue-induced reinstatement test for each group: VEH24hrCUE (n=8), NB24hrCUE (n=11) for the active lever (A) and the inactive lever (B). Re-exposure to the nicotine-paired cues (light and tone) significantly reinstated nicotine seeking in rats given vehicle pretreatment. This was not affected by pretreatment with nor-BNI, 24 hrs prior to testing. * = Significant difference across sessions in VEH24hrCUE group for active lever responses.