Exploring the interoceptive stimulus effects of nicotine and varenicline

Abstract

Learning processes associated with nicotine influence the development of addiction to tobacco products. In the present report, we are interested in the interoceptive stimulus effects of nicotine acquiring control over appetitive behaviors-specifically, reward seeking. Also of interest is the current smoking cessation drug, varenicline (Chantix®). Varenicline, with its nicotine-like stimulus effects, can decrease withdrawal and cravings for a subset of individuals addicted to nicotine, though relapse is still common. We trained rats (N=48) with nicotine (0.4 mg/kg, SC) as an excitatory stimulus (i.e., paired with sucrose) in a drug-discriminated goal-tracking (DGT) task. There was no access to sucrose on interspersed saline days. After acquisition of the initial nicotine-saline discrimination, rats were separated into four groups to test discrimination reversal and drug substitution. The control group maintained nicotine as the excitatory stimulus (NIC+). The substitution group had varenicline (1 mg/kg) replace nicotine as the stimulus paired with sucrose (VAR+). One reversal group had nicotine signal the absence of sucrose (i.e., now available on intermixed saline sessions; NIC-). The last group was similar to the NIC-group except varenicline replaced nicotine on non-reinforced sessions (VAR-). We found that varenicline fully substituted as the training stimulus when the drug-sucrose relation remained in place (VAR+). Both reversal groups acquired the new discrimination, albeit slowly and more variable for the VAR-group in comparison to NIC-. There was an effect of group during substitution testing. Specifically, nicotine fully substituted for varenicline regardless of condition. However, varenicline only partially substituted for the nicotine stimulus. At the start of extinction, responding mimicked that of the rats training condition. However, by extinction session 12, all groups maintained similarly low levels of responding. These findings show nicotine and varenicline share stimulus elements, yet the conclusion of partial to full substitution depends on the nature of the testing protocol.

Varenicline serves as the training stimulus in the drug-discriminated goal-tracking task with rats: initial evaluation of potential neuropharmacological processes

“…Notably, in the present study, nicotine evoked varenicline-like responding at doses that ranged from 0.05 to 0.4 mg/kg. This observation is consistent with past research reporting that the varenicline stimulus substitutes for a nicotine training stimulus across drug discrimination tasks (LeSage et al , 2009; Reichel et al , 2010; Thompson et al , 2019). However, the de Moura and McMahon (2017) study reported that nicotine did not substitute for the 3.2 mg/kg varenicline training dose.…”

“…The initial objective of this study was to determine whether varenicline would serve as the training stimulus in the DGT task. In a set of earlier studies, we found that 1 mg/kg varenicline seamlessly replaced the control of acquired goal-tracking behavior in rats when 0.4 mg/kg nicotine initially served as the training stimulus (Thompson et al, 2019, 2020); an outcome suggesting that varenicline might serve as a training stimulus in the DGT task. The present study confirmed that possibility.…”

“…In rats initially trained to discriminate between nicotine and saline, varenicline in substitution tests partially to fully evoke nicotine-like responding (Smith et al, 2007;LeSage et al, 2009;Reichel et al, 2010;Thompson et al, 2020). Similarly, in previous work from our lab, Thompson et al, (2019) trained rats to discriminate the nicotine (0.4 mg/kg) stimulus from saline in the DGT task, where nicotine served as the interoceptive stimulus for brief intermittent access to sucrose. On intermixed saline days, sucrose was not available.…”

Considering Drug-Associated Contexts in Substance Use Disorders and Treatment Development

“…Supporting the latter idea, animal models such as the "discriminated goal-tracking task" show that drug interoceptive stimuli can readily guide reward-seeking behavior [22,[96][97][98][99]. In these studies, the experimenter administers either a drug (e.g., nicotine) or vehicle (e.g., saline) prior to daily conditioning sessions.…”

“…If the experimental parameters are arranged in such a manner that sucrose delivery only occurs on vehicle sessions, then the opposite association can also be trained, such that rats learn to make receptacle entries on vehicle sessions and withhold receptacle entries on drug sessions [22]. Furthermore, rats previously conditioned to an interoceptive stimulus that undergo extinction sessions in which there are nonreinforced presentations of the drug interoceptive stimuli show decreases in reward-seeking behavior [97][98][99][100]. As such, understanding these learning processes may be important to consider for behavioral interventions to maintain drug abstinence.…”