Effects of Varenicline on Ethanol- and Food-Maintained Responding in a Concurrent Access Procedure

Abstract

Background Varenicline has been reported to reduce drinking in smokers, and to selectively decrease responding for ethanol versus alternatives in preclinical studies. Such selectivity may reflect potential therapeutic effects and the involvement of nicotinic receptors in ethanol reinforcement. However, these studies have been conducted with ethanol and an alternative available in isolation or in separate groups, and selectivity can depend on the context in which reinforcement occurs. Whether varenicline selectivity is maintained when ethanol and an alternative are concurrently available has not been reported. To examine the effects of varenicline on ethanol self-administration when an alternative is concurrently available, male Lewis rats (n=5) were trained to respond for ethanol and food under a concurrent FR5 FRX schedule where the fixed-ratio for food was adjusted (FR= 25 or 35) for each subject to provide matched numbers of ethanol and food deliveries during a 30-min session. Methods Doses of varenicline (0.56 – 5.6 mg/kg) or vehicle were administered 30-min before sessions. Effects of varenicline on responding across the session and during each tenth of the session were compared to responding following vehicle treatment. Results Lower doses (0.56 – 1.0 mg/kg) of varenicline increased responding for ethanol without affecting responding for food. Higher doses disrupted responding for ethanol and food similarly. Conclusions Previous reports of varenicline selectivity on ethanol-maintained responding may not generalize to other experimental conditions. The increase in responding for ethanol following lower doses might be due to enhanced ethanol reinforcement, rate-dependency, or greater perseverance on the initial, ethanol response.

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

“…We have previously shown that AT-1001 does not impact responding for food at the doses used in the present study (Toll et al, 2012). Mecamylamine and varenicline have similarly been shown to have no impact on food responding at doses we found to significantly inhibit nicotine and CSE self-administration (Levin et al, 2000;Ginsburg and Lamb, 2013). Thus, the effects observed in this study are not likely because of a general decrease in activity.…”

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in female rats

“…As detailed in Table 1, pretreatment with varenicline reduces nicotine self-administrationin pre-clinical models, (see Table 1; Chang et al , 2015; Costello et al , 2014; Funk et al , 2015; George et al , 2011; Goeders et al , 2012; Hall et al , 2015; Le Foll et al , 2012; Mello et al , 2014; O'Connor et al , 2010; Panlilio et al , 2015; Rollema et al , 2007; Scuppa et al , 2015; Wouda et al , 2011). Similarly, some studies have reported reduced intake of ethanol(see Table 2; Feduccia et al , 2014; Ginsburg and Lamb, 2013; Hendrickson et al , 2010; Kamens et al , 2010; Kaminski and Weerts, 2014; Randall et al , 2015; Sotomayor-Zárate et al , 2013; Steensland et al , 2007; Wouda et al , 2011). Interestingly, other published reports have either shown no effect on ethanol intake (Scuppa et al, 2015),or an increase in ethanol intake at certain doses (Ginsburg and Lamb, 2013).…”

“…Similarly, some studies have reported reduced intake of ethanol(see Table 2; Feduccia et al , 2014; Ginsburg and Lamb, 2013; Hendrickson et al , 2010; Kamens et al , 2010; Kaminski and Weerts, 2014; Randall et al , 2015; Sotomayor-Zárate et al , 2013; Steensland et al , 2007; Wouda et al , 2011). Interestingly, other published reports have either shown no effect on ethanol intake (Scuppa et al, 2015),or an increase in ethanol intake at certain doses (Ginsburg and Lamb, 2013). Pre-clinical research isalso mixed regarding the effects of varenicline on cocaine self-administration (see Table 3), with investigators reporting a decrease in intake (Guillem and Peoples, 2010), no effect on intake(Mello et al , 2014), oran increase in cocaine intake (Gould et al , 2011).…”

“…However, along with some studies reporting no effect or enhanced drug self-administration, there are reports that also find a non-specific effect of varenicline. Such non-specific effects includea reduction in inactive lever responding (Chang et al, 2015; George et al, 2011), a decrease in locomotor activity (Randall et al, 2015), or an attenuation of responding maintained by a non-drug reinforcer (Ginsburg and Lamb, 2013; Gould et al, 2011; O'Connor et al, 2010). Consistent with these latter reports, we found a non-specific effect of varenicline pretreatment in the self-administration phase of the present study; active lever pressing was reduced in the saline condition in a manner similar to the meth condition.…”

Relative Potency of Varenicline or Fluvoxamine to Reduce Responding for Ethanol Versus Food Depends on the Presence or Absence of Concurrently Earned Food

“…However, such selectivity appears to be be assay-dependent (Ginsburg et al, 2005; Ginsburg and Lamb, 2006, 2013). Further, many drugs that selectively reduce ethanol-maintained behavior in common preclinical assays fail or show limited effectiveness in the clinic.…”