No abstract

Rationale The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest 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 1 hr and 24 hrs 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.

The CYP2B enzyme is expressed in human and rat brain, and metabolizes many CNS-acting drugs. The gene that encodes human CYP2B6 is highly polymorphic, where the variation in brain enzyme levels could result in altered brain drug levels. CYP2B can metabolize nicotine, the main psychoactive ingredient in cigarettes; if altered brain CYP2B activity can influence nicotine brain levels, it could influence nicotine-mediated behaviors. To investigate this, a mechanism-based inhibitor selective for CYP2B, C8-xanthate (20 μg), was administered intracerebroventricularly (ICV) into the brain of rats, and 22 h later, nicotine levels were measured by in vivo microdialysis following nicotine (150 μg/kg intravenous). Brain nicotine levels from 15 to 30 min and the AUC0-45 min were both twofold higher (p<0.05) with C8-xanthate vs vehicle pretreatment; there was no difference in peripheral nicotine levels. Rats were then given ICV pretreatment with C8-xanthate/ASCF and underwent intravenous nicotine self-administration with 3.75-30 μg/kg per infusion dose. C8-xanthate pretreatment increased responding in progressive ratio (15 μg/kg per infusion dose, p<0.05). In a separate cohort, C8-xanthate increased the percentage of rats that acquired self-administration (7.5 μg/kg per infusion dose, p<0.05) from 40% after vehicle pretreatment to 100%, with no difference in peripheral nicotine levels measured at the end of behavior. In a third cohort, C8-xanthate increased the number of sessions required to meet extinction criteria (p<0.05). Together these data demonstrate that the brain CYP2B activity can influence nicotine brain levels and subsequent behaviors independent of hepatic metabolism. This suggests that human smokers with variable CYP2B brain levels could have different nicotine levels and reinforcement, which might have a role in smoking behaviors and dependence.

Operant responding for IV nicotine may rapidly come under habitual control, potentially contributing to the tenacity of tobacco use.

A marked heterogeneity exists among stressors in their ability to reinstate alcohol seeking in rats. We have reported that the pharmacological stressor yohimbine, an alpha-2 adrenoceptor antagonist, potently reinstated alcohol seeking, but FG-7142, a benzodiazepine inverse agonist was ineffective. In rats, we determined that yohimbine elicits patterns of brain expression of the mRNAs for c-fos, a marker of neuronal activation, and corticotropin-releasing factor (CRF) a stress-related peptide, distinct from that produced by FG-7142. The purpose of the present experiment is to determine if these differential effects of yohimbine and FG-7142 on regional c-fos and CRF mRNA expression generalize to another animal commonly used in alcohol research, the C57 BL/6J mouse. In comparing the results of the present study to those of our previous one, we found a number of commonalities in the patterns of activation elicited by yohimbine and FG-7142 between the two species, and some notable differences. As we found in the rat, yohimbine selectively increased c-fos mRNA in the mouse NACs, BLA and CeA. Yohimbine increased CRF mRNA only in the mouse PVN, but was without effect on CRF mRNA in extrahypothalamic sites, the BNST and CeA. This differs from what we saw in the rat, where yohimbine increased CRF mRNA in these extrahypothalamic regions, but not the PVN. The selective induction of c-fos in the NACs, BLA and CeA of mice and rats by yohimbine offers further support for the idea that activation of these structures participates in reinstatement induced by such stressors.