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. Author manuscript; available in PMC: 2024 Feb 1.
Published in final edited form as: Behav Pharmacol. 2022 Nov 3;34(1):12–19. doi: 10.1097/FBP.0000000000000707

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

Brady M Thompson 2, Matthew E Tracy 1, Y Wendy Huynh 1, Linda P Dwoskin 3, Scott T Barrett 1, Rick A Bevins 1
PMCID: PMC9908820  NIHMSID: NIHMS1833947  PMID: 36730812

Introduction

Consumption of nicotine by humans has perceptible internal (interoceptive) stimulus effects that contribute to its use liability (Perkins 1999; Murray and Bevins 2007b, a; Wooters et al. 2009; Bevins and Besheer 2014; Shoaib and Perkins 2020). The neuropharmacology of these interoceptive stimulus effects of nicotine have been widely studied in rodents using the two-operandi (e.g., lever or nose-poke) drug discrimination task and, the more recently developed drug-discriminated goal-tracking (DGT) task [for a review we suggest (Wooters et al. 2009)]. Of particular interest in the present report is the research with the partial α4β2 nicotinic acetylcholine receptor (nAChR) agonist varenicline (Rollema et al. 2007), marketed in the United States as the smoking cessation aid Chantix®. 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 a 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. After acquisition of the discrimination was evidenced by increased anticipatory dipper entries (i.e., goal tracking) only on nicotine sessions, varenicline (1 mg/kg) replaced nicotine as the stimulus now signaling sucrose-reinforced sessions. As with the substitution tests, the discrimination was readily maintained without disruption to responding (i.e., full substitution).

The research summarized to this point supports the conclusion that nicotine and varenicline have perceptible stimulus effects that at least partly overlap. Notably, published research using varenicline as the training stimulus is quite limited. We could only find one publication using a two nose-poke drug discrimination task with varenicline as the training stimulus. In that study, de Moura and McMahon (2017) trained mice to discriminate subcutaneously injected 3.2 mg/kg varenicline from saline. Mice acquired the discrimination between the varenicline and saline nose-poke holes. While acquisition data such as number of sessions to meet discrimination criteria were not presented in that paper, the discrimination once acquired remained sufficiently stable to permit extensive testing (see Discussion). The first goal of the present study was to extend the research of De Moura and McMahon to varenicline as the training drug using rats and the DGT task. While no outcome is certain, the past work described herein leads us to expect that 1 mg/kg varenicline will serve as an effective training drug in the DGT task. Although the DGT task is founded within an associative or Pavlovian framework, past research has shown excellent concordance with operant-based approaches (Charntikov et al. 2017; Wooters et al. 2009). Further, this Pavlovian-based approach provides a framework from which to think and ask different questions regarding the nature of drug stimuli (Bevins & Besheer, 2014; Murray et al. 2012).

Because 1 mg/kg varenicline served as an effective training drug in the DGT task, a second goal of the present research was to examine the neuropharmacological processes related to the varenicline stimulus. In doing so, we may gain a better understanding of the pharmacological action of varenicline that could help guide treatment geared towards tobacco-cessation. That is, unlike past work described herein and elsewhere drawing inferences regarding the nature of the varenicline stimulus via animals trained on a nicotine stimulus (e.g., Wooters et al., 2009), we can now ask whether a particular ligand has stimulus effects similar to varenicline. A different question that may lead to different answers. To this end, we established the varenicline dose-effect curve and generalization curve for nicotine. Further, we investigated specific nicotinic and non-nicotinic pharmacological agents to determine the degree to which they evoked varenicline-like responding (i.e., substitution). These other compounds included the tobacco alkaloid, nicotine metabolite and β4 as well as β2 agonist nornicotine (Dwoskin et al., 2001; Green et al., 2001; Smith & Stolerman, 2009), the stoichiometrically selective α4β2* antagonist and partial agonist sazetidine-A (Zwart et al., 2008), the α7 agonist PHA-543613 (Wishka et al. 2006), and the norepinephrine and dopamine reuptake inhibitor, nAChR antagonist, and FDA approved smoking cessation aid bupropion (Ferris & Beaman, 1983; Shoaib, Sidhpura, & Shafait, 2003).

Methods

Animals

Male Sprague-Dawley rats (N = 10) were obtained from Envigo at 7 to 8 weeks of age. TEK-Fresh® (Envigo, Indianapolis, IN) bedding was used in polycarbonate home cages (48.3 × 26.7 × 20.3 cm [l × w × h]) where each rat was housed individually. Upon arrival, rats were handled daily for one week to acclimate them to the colony and personnel. Before the start of the study, food was restricted to maintain weights at 85% free-feed body weight (average ad lib feed weight = 291 g). This weight was increased by 2 g each month. The colony room was temperature- and humidity-controlled with lights on a 12-hour light/dark schedule (lights on at 6 AM). All protocols were approved by the University of Nebraska-Lincoln Institutional Animal Care and Use Committee.

Apparatus

The experiment was conducted (7 days/week) in an experimental room outfitted with 10 Med-Associates, Inc. (St. Albans, VT) chambers with rod flooring, polycarbonate walls on the front and back, and aluminum right- and left-side walls (Model: ENV-008CT; 30.5 × 24.1 × 21.0 cm [l × w × h]). Each chamber was housed in a light- and sound-attenuating cubicle with a fan affixed to the top-right side to provide airflow and increase sound attenuation. A recessed dipper receptacle (5.2 × 5.2 × 3.8 cm; [l × w × h]) was positioned 3 cm above the rod floor in the middle of the right-side wall. An infrared beam placed 1.2 cm inside the receptacle recorded head entries. A motorized dipper arm located outside the dipper receptacle raised and lowered a 0.1-ml cup of 26% sucrose solution (w/v).

Drugs

Varenicline tartrate (see later sections for doses), sazetidine-A, bupropion hydrochloride, and PHA-543613 hydrochloride were provided to us through the NIDA Drug Supply Program (RTI International [Research Triangle Park, NC]). S-(−)-Nornicotine fumarate was provided by Girindus America, Inc. (Cincinnati, OH). Drugs were dissolved in 0.9% saline. The pH of the nicotine solution was adjusted to 7.0 ± 0.2 with sodium hydrochloride. All drug and saline solutions were injected subcutaneously (SC) at a volume of 1 ml/kg. Nicotine doses are expressed as base, while the remaining drugs are expressed as salts.

Discrimination Training

For discrimination training, each rat received a unique order of varenicline and saline days with the condition that no more than two consecutive days with the same stimulus occurred. On varenicline days, rats received a SC injection of 1 mg/kg varenicline 15 min before chamber placement and the start of the session. On these days, rats were given interspersed, non-contingent, presentations of liquid sucrose made available for 4 sec in the dipper receptacle. The first sucrose presentation occurred 124 to 152 sec after the start of the session (average = 140 sec). All following presentations in the 20-min session occurred on a variable time 25-sec schedule of reinforcement (range 4 to 80 sec). Saline days were similar to varenicline days except that saline was injected 15 min before the session and sucrose was withheld (i.e. the dipper was not operated) throughout the 20-min session. Discrimination training was conducted for 60 total days (i.e., 30 varenicline and 30 saline sessions) to ensure goal-tracking rates were stable before moving to the testing phase. Timing of the varenicline injection relative to the start of the session, as well as the training dose of varenicline, was based on Thompson et al. (2019, 2020).

Dose Effect and Substitution Testing

After discrimination training, all rats began a repeating five-day testing cycle. This cycle included four discrimination training days as described earlier (2 varenicline and 2 saline days). If the discrimination was maintained, then a brief 140-sec test of the assigned solution was conducted on the fifth day of the cycle. Rats qualified for testing when pre-sucrose dipper-entry rates were 0.01 entries per sec higher on varenicline days when compared to dipper-entry rates on saline days (Murray et al. 2011). Test doses and the time from injection to the start of the test session were based on the work of Charntikov et al. 2017 (see Table 1 in that article). The injection to the start intervals were as follows: 5 min for nicotine; 15 min for varenicline, bupropion, and nornicotine; and 10 min for PHA-543613 and sazetidine-A. Testing cycles were conducted in the following order: nicotine (0.025, 0.05, 0.1, 0.2, 0.4 mg/kg) and varenicline (0.1, 0.3, 1, 3 mg/kg); then sazetidine-A (0.3, 1, 3 mg/kg); then bupropion (10, 20, 30 mg/kg); then nornicotine (0.3, 1, 3, 10 mg/kg); and finally PHA-543613 (1, 3, 10 mg/kg). Each rat received a unique order for each drug using a Latin-square design. When a rat failed to meet the testing criterion, it remained in the home cage for the test day.

Dependent measures and analyses

The dependent measure for discrimination training was dipper entries per sec before the first sucrose presentation on varenicline sessions or an equivalent time on non-reinforced saline sessions. Accordingly, the dependent measure was recorded prior to the activation of the dipper. We use this early session measure of conditioning rather than total responding in the 20-min session because it avoids any goal tracking prompted by sucrose deliveries. A rate measure was used because the time to the first sucrose delivery varied across sessions. For analysis of discrimination training, we used a two-way repeated analysis of variance (ANOVA) with Session and Drug (varenicline vs saline) as repeated factors and using a Holm-Sidak correction factor.

To be consistent across phases, we used rates of responding as the dependent measure for the 140-sec test sessions. In the testing phase, we asked whether the test drug (e.g., nornicotine or bupropion) substitutes for the varenicline training stimulus. To answer this question, we needed a varenicline and saline benchmark in which to compare the goal tracking controlled by each dose of the test drug. To calculate these benchmarks, we used the average rate of dipper entries before the first sucrose delivery for the previous two varenicline days and the previous two saline days that occurred before testing each dose of the drug — 1–10 mg/kg for nornicotine, 10–30 mg/kg for bupropion, etc. A similar approach was used for calculating the saline benchmark. These key benchmark values cannot be included in an omnibus ANOVA. Accordingly, we went directly to statistically assessing substitution by limiting the contrasts with paired t-tests (cf. McGovern et al. 2011; Wilkinson et al. 2010). Limiting contrasts to just the benchmarks focused the analyses on key predictions while at the same time decreasing potential Type I errors (e.g., no comparison of a substitution dose with other test doses in the dose-effect curve were conducted). Full substitution was declared when responding evoked by the test dose was greater than saline but did not differ from the 1 mg/kg varenicline benchmark (training) dose. Partial substitution was defined as conditioned responding significantly higher than saline yet significantly lower than that evoked by 1 mg/kg varenicline. One rat was removed from the study when he developed an abdominal tumor. Thus, the final sample size for all analyses was nine.

Results

Discrimination Training

As shown in Figure 1, rats learned to discriminate 1 mg/kg varenicline from saline. There was a main effect of Session [F(29, 232)=4.43, p<0.0001] and Drug [F(1, 8)=22.95, p=0.0014], as well as a significant Drug x Session interaction [F(29, 232)=4.273, P<0.0001]. Elevated dipper entries on varenicline sessions relative to saline sessions occurred on sessions 8, 13, 15–17, 19–22, and 24–30 (ps ≤ 0.02). Intervening training days during the substitution testing cycles are shown on the right side of Figure 1 (after the break in the X axis). These data were not analyzed with an ANOVA because the total number of rats contributing to a data point decrease later in the experiment as some rats qualified more frequently than others thus completing the study earlier.

Figure 1.

Figure 1

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displays acquisition data across all sessions of varenicline versus saline training days. The dotted line represents the beginning of the testing phase. All sessions shown after the line display responding during the qualification sessions. Data for significant differences in acquisition days are reported in the results section, due to differences in group size as qualification progressed analysis for the sessions after this line are restricted. Rats that qualified for all tests earliest finished before those who did not so subject size decreases as sessions progress (See Figure 2 for varenicline and saline qualification data for each drug).

Varenicline

Figure 2A shows dipper entries for the varenicline dose-effect curve. Relative to saline, there was significantly higher rates of conditioned responding for 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg varenicline (ts≥2.958; ps≤0.014). Notably, the highest tested dose of varenicline (3 mg/kg) did not differ from saline (t=1.358; p=0.206). Dipper entries did not differ between 1 mg/kg varenicline and 0.1, 0.3, and 3 mg/kg varenicline (ts≤1.88; ps≥0.08).

Figure 2.

Figure 2

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displays dose effect and substitution testing data as follows: A) Varenicline dose-effect testing; B) Nicotine substitution testing; C) Sazetidine-A substitution testing; D) Bupropion substitution testing; E) Nornicotine substitution; F) PHA-543613 substitution testing. *Asterisk denotes significant difference from saline; Τ denotes significant differences from both saline and the 1 mg/kg varenicline training dose; Ŧ Symbol denotes variable responding by rats indicating no difference from either stimulus.

Nicotine

Figure 2B displays dipper entries for the nicotine substitution tests. The discrimination remained robust as dipper entries evoked by 1 mg/kg varenicline were significantly higher than saline (t=3.381; p=0.008). Responding was not significantly different from saline for 0.025 mg/kg nicotine (t=1.684; p=0.125). In contrast, nicotine-evoked responding was higher than saline for 0.05, 0.1, 0.2, and 0.4 mg/kg nicotine (ts≥2.483; ps≤0.036). For all doses, nicotine-evoked responding did not differ significantly from 1 mg/kg varenicline (ps≥0.115). Overall, we interpret these data to indicate full substitution by 0.05, 0.1, 0.2, and 0.4 mg/kg nicotine for the varenicline stimulus.

Sazetidine-A

Figure 2C displays dipper entries from sazetidine-A substitution tests. The discrimination remained as dipper entries were significantly higher for 1 mg/kg varenicline compared to saline (t=3.941; p=0.002). Dipper entries did not differ from 1 mg/kg varenicline for 0.3 and 1.0 mg/kg sazetidine-A (ps≥0.280) but were significantly lower for 3 mg/kg sazetidine-A (t=−4.534; p=0.001). Regardless of sazetidine-A dose, dipper entries controlled by sazetidine did not differ from saline (ps≥0.111). Albeit variable across individuals, we interpret these data to indicate partial substitution by 0.3 and 1 mg/kg sazetidine-A for the varenicline stimulus.

Bupropion

Figure 2D displays dipper entries for the bupropion substitution tests. Again, the discrimination remained robust as dipper entries evoked by 1 mg/kg varenicline were higher than saline (t=5.077; p=0.001). Dipper entries evoked by bupropion were significantly lower than 1 mg/kg varenicline for 10, 20, and 30 mg/kg bupropion (ts≤−3.701; ps≤0.003). Dipper entries were significantly higher than saline for 10 and 30 mg/kg bupropion (ts≥2.237; ps≤0.048), but not 20 mg/kg bupropion (t=1.547; p=0.151). From the strict perspective of the analyses, this data pattern suggests weak partial substitution of 10 and 30 mg/kg bupropion for the varenicline stimulus. However, from a behavioral or pharmacological perspective, it seems less clear how meaningful is such weak substitution.

Nornicotine

Figure 2E displays dipper entries for the nornicotine substitution tests. The discrimination was maintained with higher responding relative to saline at 1 mg/kg varenicline (t=4.136; p=0.003). Dipper entries were significantly lower than those evoked by 1 mg/kg varenicline for 0.3, 1, and 10 mg/kg nornicotine (ts≤−2.274; ps≤0.041). Dipper entries did not differ between varenicline and 3 mg/kg nornicotine (t=−2.007; p=0.070). Conversely, dipper entries were higher than saline for both 1 and 3 mg/kg nornicotine (ts≥2.524; ps≤0.032), but not for saline or 0.3 and 10 mg/kg nornicotine (ps≥0.368). We interpret these data to indicate full substitution by 3 mg/kg nornicotine and partial substitution by 1 mg/kg nornicotine for the varenicline stimulus.

PHA-543613

Figure 2F displays dipper entries from the PHA-543613 substitution tests. The discrimination remained robust as 1 mg/kg varenicline-evoked responding was higher than saline (t=3.971; p=0.004). Dipper entries were significantly lower than 1 mg/kg varenicline for all PHA-543613 doses (ts≤−3.986; ps≤0.004). Regardless of dose, dipper entries for PHA-543613 did not differ from saline (ps≥0.19). These data are interpreted as indicating that PHA-543613 does not share stimulus effects with varenicline.

Discussion

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. Varenicline at 1 mg/kg served as the original training stimulus and initial training with nicotine was not required. This observation corroborates the work by de Moura and McMahon (2017) who found that 3.2 mg/kg varenicline served as the training drug with a 2-nose poke operant drug discrimination task in mice. We also extended their work to Sprague-Dawley rats and to the DGT task. The latter extension adds to the growing literature supporting the utility of the different variants of the DGT task to study drug stimuli and associated processes (cf. Murray et al. 2012; Wooters et al. 2009).

Given that rats acquired and maintained the discrimination between varenicline and saline in the present study, we had the opportunity to conduct generalization tests with varenicline and substitution tests with nicotine, sazetidine-A, bupropion, nornicotine, and PHA-543613. Doing so allowed us to further extend the research of de Moura and McMahon (2017) and to explore potential neuropharmacological factors contributing to the interoceptive stimulus effects of varenicline. For the varenicline generalization test, we found an inverted-U shaped function with the training dose of 1 mg/kg and the lower 0.3 mg/kg dose evoking peak conditioned responding; 0.1 mg/kg varenicline partially substituted for the training dose. The highest test dose of varenicline (3 mg/kg) did not evoke any goal tracking (i.e., responding comparable to saline).

One possible explanation for the lack of goal tracking at the higher dose is that acute administration of 3 mg/kg varenicline has motor impairment effects that interfere with generalization of the conditioned response controlled by the training dose. For several reasons, general motor impairment seems an unlikely explanation. First, our conditioning chambers are equipped with an infrared photobeam that bisects the chamber (see Reichel et al. 2010). The Med-Associates code running the test sessions collected the number of beam breaks in the 140-sec generalization test. Upon extracting and summarizing those data, we found no difference between saline (Mean = 54.7) versus 3 mg/kg varenicline (Mean = 61.6) in the number of beam breaks (t<1). Notably, this outcome directly replicates an earlier finding from our lab. Using the same protocol as the present study, varenicline at 3 mg/kg substituted fully for the nicotine training stimulus and, as in the present study, it did not affect chamber activity relative to a saline benchmark (Reichel et al. 2010). Finally, LeSage et al. (2009) reported that 3 mg/kg varenicline partially substituted for the nicotine training stimulus without disrupting response rates on the active (drug-appropriate) lever. The converging evidence across studies, labs, and tasks does not support a motor impairment account regardless of the pattern of responding evoked by varenicline. The more likely explanation is that the prevailing stimulus effects of 3 mg/kg varenicline in our standard acute testing procedure do not sufficiently overlap with the 1 mg/kg dose to evoke conditioned responding. An outcome that may not be so surprising when considering the complex neuropharmacological actions of varenicline (Mihalak et al., 2006; see later).

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. This difference—substitution of nicotine for 1 mg/kg varenicline (present study) versus lack of nicotine substitution for 3.2 mg/kg varenicline (de Moura and McMahon)—could be taken as further support of our earlier suggestion that the stimulus effects of an acute injection of 3 mg/kg varenicline differ from the 1 mg/kg dose (see previous paragraph). However, we recommend taking some caution in accepting this as definitive evidence. Namely, there are many procedural differences we could point to as being responsible for this difference in nicotine substitution – species, discrimination training task, substitution testing protocol, training dose, etc. While these are all potential contributing factors, picking any single one would be sheer speculation on our part. Rather, we would highlight the need to replicate and extend the work described herein and that of de Moura and McMahon. For example, would we find a lack of acute nicotine substitution had we used 3.2 mg/kg varenicline as the training dose in the DGT task? Similarly, would results parallel our findings if the mice in a two nose-poke hole discrimination task had 1 mg/kg varenicline as the training dose?

Varenicline is a partial agonist for the α4β2–containing nAChRs as well as a potent agonist at α7 nAChRs (Mihalak et al. 2006). PHA-543613 did not substitute for 1 mg/kg varenicline indicating that α7 nAChRs do not contribute to the interoceptive effects of the varenicline stimulus in the DGT task. Further, the lack of substitution by bupropion suggests that norepinephrine and dopamine do not contribute to the stimulus effects of varenicline. In contrast, we found partial to full substitution for the varenicline stimulus by nornicotine and, as described earlier, nicotine. Each of these ligands has a distinct binding profile for different nAChR subtypes. For example, the rank-order efficacy for nicotine is α4β2 > α3β4 > α3β2 (Wooters et al. 2009); nornicotine is α3β4 > α3β2 > α5β2 > α2β2β3 (Papke et al. 2007). While other α subunits may contribute to the substitution for varenicline, consideration of these binding profiles suggests an important role for the β2 subunits. Future work will need to focus on parsing out the relative contribution of different subtypes using more precise pharmacological and neuroscientific techniques.

The atypical selective α4β2* nAChR antagonist/partial agonist ligand sazetidine-A produced a large variance in varenicline-like responding across rats. Such individual variation could be attributed to differences in its intrinsic activity to different stoichiometrically arranged α4β2-containing receptors. With nAChRs containing the pentameric arrangement of two α4 and three β2 subunits, sazetidine-A functions as an agonist. However, it functions as an antagonist with arrangements containing three α4 and two β2 subunits (Zwart et al. 2008). Perhaps the rats that displayed varenicline-like responding when tested with sazetidine-A had a different distribution or population of agonist versus antagonist arrangements of the α4β2-containing receptors.

Varenicline is an important non-nicotine therapeutic for aiding in smoking cessation (Rollema et al. 2007). In the present paper, we found that this α4β2* nAChR partial agonist at 1 mg/kg had salient interoceptive stimulus effects that acquired control of an appetitive conditioned response (i.e., goal tracking). The neuropharmacological processes that compose the varenicline stimulus overlap with the stimulus element that contribute to the nicotine stimulus and the stimulus effects of its metabolite nornicotine. Such overlap likely contributes to the therapeutic efficacy of varenicline (cf. Rollema et al. 2007; Reichel et al. 2010). Bupropion, another non-nicotine therapeutic for aiding in smoking cessation, did not evoke varenicline-like responding. An outcome that we take to indicate a limited role for dopamine or norepinephrine elements in the stimulus effects of varenicline. Finally, on the nAChR subunits explored in the present study, the β2 subunit seems to contribute to the stimulus effects of varenicline; this was not the case for α7 nAChRs. The importance of this β subunit is consistent with a growing literature implicating the β2 subunit in liability for nicotine use and misuse [for a recent review see Picciotto and Kenny (2021)].

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