Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats

Abstract

Background Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse. Methods Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone+light), the anxiogenic drug yohimbine (2.5 mg/kg, IP), a priming injection of nicotine (0.3 mg/kg, SC), or combinations of drug+cues to reinstate nicotine-seeking. Results Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests. Conclusions These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.

Comparison of the Reinforcing Properties of Nicotine and Cigarette Smoke Extract in Rats

“…Furthermore, there were significant differences in patterns of reinstatement of CSE-and nicotine-seeking behaviors. Reinstatement to nicotine-seeking behavior was similar to that reported previously, with additive reinstatement to cues and to a pharmacological stressor, yohimbine (Feltenstein et al, 2012). In contrast, animals that had self-administered CSE reinstated more robustly to stress alone, with no additional effect of cue exposure.…”

“…Reinforced behavior was then extinguished by removal of drug and associated cues until responding was reduced to p20% of the last day of drug self-administration and for a minimum of 5 days. Reinstatement testing then began using three conditions in a randomized order that have been shown previously to reinstate responding for nicotine (Feltenstein et al, 2012): Cues only, Stress only (yohimbine (2.5 mg/kg, i.p., a pharmacological stressor (See and Waters, 2010)) 30 min before testing), and Cues þ Stress. Between reinstatement tests animals were returned to extinction conditions for a minimum of 2 days or until extinction criteria were met.…”

Behavioral effects of phencyclidine on nicotine self-administration and reinstatement in the presence or absence of a visual stimulus in rats

“…Yohimbine, an α2 adrenergic receptor antagonist, has been widely used as a pharmacological stressor as it induces an increase in stress-like behaviors in both human and non-human animals (Li et al 2012; Stine et al 2002; Davis et al 1979; Charney et al 1983). Yohimbine has been shown to increase drug-seeking behaviors in a reinstatement model for drugs such as methamphetamine, cocaine, and nicotine (Shepard et al 2004; Lee et al 2004; Feltenstein et al 2012). Perhaps the interoceptive stimulus effects of yohimbine might be similar to the effects of phencyclidine and the reinstatement reflects this generalization between yohimbine and PCP.…”

Corticotropin releasing factor: A key role in the neurobiology of addiction

“…Consistent with this hypothesis, systemic injection of yohimbine, an α 2 adrenoceptor antagonist that induces stress-and anxiety-like responses (Bremner et al, 1996), can induce alcohol and heroin craving in human drug addicts (Stine et al, 2002;Umhau et al, 2011). Moreover, yohimbine can reinstate drug-seeking behavior in rats (Shepard et al, 2004;Feltenstein et al, 2012) and monkeys (Lee et al, 2004), as well as the seeking of alcohol (Marinelli et al, 2007) or palatable food in rats (Ghitza et al, 2006). Supporting a role for CRF systems in this relapse mechanism, yohimbine-induced reinstatement of substance-seeking can be prevented by systemic pretreatment with brain-penetrant CRF 1 receptor antagonists or intracranial pretreatment with peptide CRF receptor antagonists (Le et al, 2002;Marinelli et al, 2007;Shalev et al, 2010).…”