Extended nicotine self‐administration increases sensitivity to nicotine, motivation to seek nicotine and the reinforcing properties of nicotine‐paired cues.

Abstract

An array of pharmacological and environmental factors influence the development and maintenance of tobacco addiction. The nature of these influences likely changes across the course of an extended smoking history, during which time drug seeking can become involuntary and uncontrolled. The present study used an animal model to examine the factors that drive nicotine-seeking behavior after either brief (10 days) or extended (40 days) self-administration training. In Experiment 1, extended training increased rats' sensitivity to nicotine, indicated by a leftward shift in the dose-response curve, and their motivation to work for nicotine, indicated by an increase in the break point achieved under a progressive ratio schedule. In Experiment 2, extended training imbued the nicotine-paired cue with the capacity to maintain responding to the same high level as nicotine itself. However, Experiment 3 showed that the mechanisms involved in responding for nicotine or a nicotine-paired cue are dissociable, as treatment with the partial nicotine receptor agonist, varenicline, suppressed responding for nicotine but potentiated responding for the nicotine-paired cue. Hence, across extended nicotine self-administration, pharmacological and environmental influences over nicotine seeking increase such that nicotine seeking is controlled by multiple sources, and therefore highly resistant to change.

Varenicline Targets the Reinforcing-Enhancing Effect of Nicotine on Its Associated Salient Cue During Nicotine Self-administration in the Rat

“…Our study also complements previous findings in clarifying the reinforcing-enhancing effects of Varenicline on a visual cue: namely, that these effects are only observed when individuals have been previously exposed to nAChR agonists. Contrary to our study, Clemens et al (2017) and Barrett et al (2018) showed that acute Varenicline increased the self-administration of a visual cue alone in the absence of nicotine. Furthermore, Levin et al (2012) briefly reports in drug-naïve animals, the reinforcing-enhancing effects of Varenicline on visual cues.…”

“…However, and differently to our case, in these studies, rats had been previously exposed to either nicotine or Varenicline. In Clemens et al (2017), rats had been previously trained for nicotine + cue self-administration and Varenicline tested after seven self-administration of the cue alone, through a nicotine extinction-like procedure. In Barrett et al (2018), Varenicline was tested following a history of repeated passive exposure to nicotine administered after the cue self-administration sessions.…”

Enhancing effect of menthol on nicotine self-administration in rats

“…Rats exhibited reliable and dose-dependent lever-press responses for nicotine self-administration. An inverted U-shaped dose-response curve was observed, which is consistent with other rat studies (Clemens et al 2015; Donny et al 1995; Hopkins et al 2012; Watkins et al 1999). Importantly, the present study further demonstrated that intraperitoneal pretreatment with menthol shifted the nicotine dose-response curve to the left.…”

Rats choose high doses of nicotine in order to compensate for changes in its price and availability

“…In contrast, as in the present study, the rate of free‐access nicotine self‐administration varied considerably within a session (and see Clemens et al . ()), with the combination of frequency and dose bringing the estimated level of blood nicotine to an asymptote, and then maintaining it around that asymptote. These distinct within‐session self‐administration patterns might imply differences in the degree to which nicotine and cocaine seeking are controlled by the negatively and positively reinforcing effects of each drug when each is freely available.…”

“…These doses were selected to include (30 μg/kg/infusion) and bracket (15 and 60 μg/kg/infusion) that which typically produces the highest rate of responding on a nicotine dose–response curve (Clemens et al . ).…”