Chronic Nicotine Exposure Initiated in Adolescence and Unpaired to Behavioral Context Fails to Enhance Sweetened Ethanol Seeking

Abstract

Nicotine use in adolescence is pervasive in the United States and, according to the Gateway Hypothesis, may lead to progression towards other addictive substances. Given the prevalence of nicotine and ethanol comorbidity, it is difficult to ascertain if nicotine is a gateway drug for ethanol. Our study investigated the relationship between adolescent exposure to nicotine and whether this exposure alters subsequent alcohol seeking behavior. We hypothesized that rats exposed to nicotine beginning in adolescence would exhibit greater alcohol seeking behavior than non-exposed siblings. To test our hypothesis, beginning at P28, female rats were initially exposed to once daily nicotine (0.4 mg/kg, SC) or saline for 5 days. Following these five initial injections, animals were trained to nose-poke for sucrose reinforcement (10%, w/v), gradually increasing to sweetened ethanol (10% sucrose; 10% ethanol, w/v) on an FR5 reinforcement schedule. Nicotine injections were administered after the behavioral sessions to minimize acute effects of nicotine on operant self-administration. We measured the effects of nicotine exposure on the following aspects of ethanol seeking: self-administration, naltrexone (NTX)-induced decreases, habit-directed behavior, motivation, extinction and reinstatement. Nicotine exposure did not alter self-administration or the effectiveness of NTX to reduce alcohol seeking. Nicotine exposure blocked habit-directed ethanol seeking. Finally, nicotine did not alter extinction learning or cue-induced reinstatement to sweetened ethanol seeking. Our findings suggest that nicotine exposure outside the behavioral context does not escalate ethanol seeking. Further, the Gateway Hypothesis likely applies to scenarios in which nicotine is either self-administered or physiologically active during the behavioral session.

Effects of nicotine conditioning history on alcohol and methamphetamine self-administration in rats

“…Having a nicotine conditioning history did not affect the sucrose fading phase or maintenance of alcohol self-administration in female or male rats. This finding is consistent with a previous study assessing nicotine exposure in adolescence that found that nicotine exposure alone did not enhance alcohol self-administration (Madayag et al 2017). However, several studies have shown that nicotine administered immediately prior to alcohol self-administration sessions increases alcohol-seeking (Larraga et al 2017;Le et al 2014;Smith et al 1999), suggesting that proximity of nicotine treatment to self-administration sessions is important when assessing nicotine effects on alcohol self-administration.…”

Nicotine affects ethanol-conditioned taste, but not place, aversion in a simultaneous conditioning procedure

“…The chronic nicotine pre-exposure and pre-treatment was as follows: (a) on lickometer training sessions days three, four and five, the rats were injected with their assigned nicotine treatment (0.0 or 0.4 mg/kg nicotine, 15 min prior to placement in the Davis rig), (b) during conditioning days 1 to 8 the rats were injected with their assigned nicotine treatment (0.0 or 0.4 mg/kg nicotine) 15 min prior to the commencement of the conditioning procedures. The dose of nicotine was selected based on recent studies that assessed the effects of nicotine pre-exposure (Madayag, Czarnecki, Wangler, & Robinson, 2017) or pre-treatment (Maddux & Chaudhri, 2017) upon ethanol-seeking in rats. This regimen of nicotine dosing was not only chosen to measure the chronic effects of nicotine treatment but also served to ensure that nicotine did not serve as an US in the CTA and CPA conditioning as animals received substantial non-contingent exposure to nicotine outside of conditioning trials.…”

Nicotine as a discriminative stimulus for ethanol use

“…These effects are often thought to be due to nicotine increasing ethanol seeking and use by directly enhancing the reinforcing effect of ethanol (Doyon et al, 2013). For example after a history of nicotine exposure outside of the context where drinking occurs, nicotine re-exposure increases ethanol consumption and preference, but does not affect cue-induced reinstatement of ethanol responding (Clark et al, 2001; Ericson et al, 2000; Kemppainen et al, 2009; Leão et al, 2015; Madayag et al, 2017; c.f. Sharpe and Samson, 2002).…”