Additionally, currently data (Donny, Caggiula, Weaver, Levin, & Sved, 2011; Harris, Pentel, Burroughs, Staley, & Lesage, 2011) suggest that withdrawal of nicotine may lead to different outcomes at earlier, as opposed to later, points in the timeline of withdrawal. The current investigation, however, was limited to 2 days of precipitated withdrawal; therefore, a complete characterization calls for a more temporally extended assessment. In both experiments, continuous nicotine initially resulted in reinforcement enhancement, which was similar in magnitude to that observed in our previous studies with intermittent nicotine. However, the enhancement effect dissipated over days, and by 2 weeks (i.e., 10 sessions and 4 weekend days), the nicotine-exposed group did not significantly differ from saline.

This attenuation of the reinforcement-enhancing effects of nicotine has not previously been observed in experiments involving intermittent nicotine exposure (Caggiula, Donny, Chaudhri, et al., 2002; Donny et al., 2003; Palmatier et al., 2006). The attenuation observed in the current experiments may be indicative of tolerance to the reinforcement-enhancing effects of nicotine or extinction of an association between nicotine and the VS established during the injection phase. The latter explanation is similar to one proposed by Rose, Behm, Westman, and Kukovich (2006), suggesting that transdermal nicotine may facilitate extinctions of the conditioned reinforcing properties of smoking stimuli. This interpretation is bolstered by the observation that chronic nicotine had the most robust effect in animals that previously received pre-session acute nicotine injections.

Future studies should attempt to disentangle possible extinction processes from an attenuation of the enhancement effect. Likewise, the interpretation of the attenuation based on tolerance to the enhancement will require a thorough dose�Cresponse assessment. Experiment 1 included rats that all had a history of intermittent nicotine exposure prior to minipump implantation to demonstrate the development of the reinforcement enhancement effect, which until the current experiment had only been observed with intermittent dosing regimens (e.g., s.c. and intravenous routes of administration). Experiment 2 was designed to address the effects of nicotine history while simultaneously increasing statistical power regarding effects related to chronic nicotine treatment and mecamylamine antagonism.

Although results Dacomitinib across pre-treatment conditions were qualitatively similar, the effects of continuous nicotine and mecamylamine were more robust in animals with a history of pre-session nicotine when compared with those with post-session nicotine or saline history. Future studies should further examine the role of nicotine history as a potential moderator of the effects of continuous, chronic nicotine exposure and subsequent withdrawal from nicotine.

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