Reward-enhancing effects of d-amphetamine and its interactions with nicotine were greater in female rats and persisted across schedules of reinforcement

Abstract

Nicotine enhances the value of environmental stimuli and rewards, and reward enhancement can maintain nicotine consumption. Stimulants such as d-amphetamine are misused more by women and are commonly co-used with nicotine. d-Amphetamine potentiates nicotine’s effects in human and animal research. To date, there are no published studies examining this interaction in a reward-enhancement task. The current study sought to investigate the reward-enhancing effects of nicotine alongside and coadministered with d-amphetamine. Further, we evaluated the persistence of reward enhancement across ratio and temporal schedules of reinforcement. We used 10 male and 10 female Sprague–Dawley rats. Enhancement was assessed within subjects by examining active lever pressing for a visual stimulus reinforcer on variable ratio 3, variable interval 30 s and variable time 30 s – variable ratio 3 schedules. Before 1-h sessions, rats received one injection of saline, 0.1 or 0.3 mg/kg d-amphetamine and one of saline or 0.4 mg/kg nicotine, making six possible drug combinations (saline + saline, saline + nicotine, 0.1 d-amphetamine + aline, 0.1 d-amphetamine + nicotine, 0.3 d-amphetamine + saline and 0.3 d-amphetamine + nicotine) experienced in a randomized order by each rat. When d-amphetamine was coadministered with nicotine, we found an interaction effect on reward enhancement that persisted across schedules of reinforcement. Males and females exhibited reward enhancement by 0.3 d-amphetamine, while only females showed reward enhancement by 0.1 d-amphetamine. Further, females responded more for the visual stimulus than males in all d-amphetamine conditions. Future studies should assess how reward enhancement is involved in high nicotine-amphetamine comorbidity rates and enhanced amphetamine misuse in women.

The co-use of nicotine and prescription psychostimulants: A comprehensive review of their behavioral and neuropharmacological interactions

“…Of the few preclinical studies that did examine sex as a biological variable, all examined amphetamine or bupropion. Highlighting our concern, each of the preclinical studies powered to assess sex differences found greater effects in women or female rodents (Collins et al, 2004;Íbias and Nazarian, 2020;McNealy et al, 2022McNealy et al, , 2021Zakiniaeiz et al, 2019). This work is consistent with females and human women being more sensitive to most behavioral effects of psychostimulants (Becker and Koob, 2016;Camp and Robinson, 1988;Milesi-Hallé et al, 2007).…”

“…We have conducted two studies in our laboratory examining the chronic and acute interactions between nicotine and d-amphetamine on reward-enhancement. Both studies found that acutely co-administered nicotine and d-amphetamine interacted to additively enhance responding maintained by a visual stimulus reinforcer (McNealy et al, 2022(McNealy et al, , 2021.…”

“…Reward-enhancement can be measured by examining operant response rates for weakly reinforcing visual stimuli. In this case, the animal is injected with a drug or vehicle control, then placed in a conditioning chamber (much like the one in Figure 1c) and allowed to respond for a weak to moderate reinforcer such as low concentration sucrose (Barret and Bevins, 2013) or a brief light presentation (Barrett and Bevins, 2012;McNealy et al, 2021;Raiff and Dallery, 2008). In these studies, nicotine and other psychostimulants produce roughly two-fold increases in responding for visual stimuli (Barrett and Bevins, 2012;Winterbauer and Balleine, 2007).…”