Sex Differences in the Reward-Enhancing Effects of Nicotine on Ethanol Reinforcement: A Reinforcer Demand Analysis

Abstract

Background: Alcohol is often consumed with tobacco, and dependence to alcohol and tobacco are highly comorbid. In addition, there are differences in the prevalence of nicotine- and alcohol-abuse between the sexes. Nicotine produces enhancing effects on the value of other reinforcers, which may extend to alcohol.

Methods: Male and female Wistar rats were trained to self-administer 15% ethanol solution in 30-minute sessions. Once ethanol self-administration was established, demand for ethanol was evaluated using an exponential reinforcer demand method, in which the response cost per reinforcer delivery was systematically increased over blocks of several sessions. Within each cost condition, rats were preinjected with nicotine (0.05, 0.1, 0.2, or 0.4 mg/kg base, SC) or saline 5 minutes before self-administration sessions. The effects of nicotine dose and biological sex were evaluated using the estimates generated by the reinforcer demand model.

Results: Under saline conditions, males showed greater sensitivity to ethanol reinforcement than females. Nicotine enhanced the reinforcement value of alcohol and this varied with sex. In both sexes, 0.4 mg/kg nicotine decreased intensity of ethanol demand. However, 0.05, 0.1, and 0.2 mg/kg nicotine decreased elasticity of ethanol demand in females, but not in males.

Conclusions: Nicotine enhances ethanol reinforcement, which may partially drive comorbidity between nicotine-abuse and alcohol-abuse. Males showed signs of greater ethanol reinforcement value than females under saline conditions, and nicotine attenuated this effect by increasing ethanol reinforcement value in the females. These findings highlight that a complete understanding of alcohol-abuse must include a thorough study of alcohol use in the context of other drug use, including nicotine.

Implications: Nicotine dose dependently enhances the alcohol reinforcement value in a manner that is clearly influenced by biological sex. Under saline baseline conditions, males show lower elasticity of demand for alcohol reinforcement than females, indicative of greater reinforcement value. However, nicotine attenuated this difference by enhancing alcohol reward in the females. Specifically, low-to-moderate doses (0.05-0.2 mg/kg) of nicotine decreased elasticity of alcohol demand in female rats, increasing the perseverance of their alcohol taking behavior. These data indicate that the well-documented reward-enhancing effects of nicotine on sensory reinforcement extend to alcohol reinforcement and that these vary with biological sex.

Figure 1.

Mean active lever-presses (±1 SEM) as a function of fixed-ratio (FR) schedule in the female (left panel) and male (right panel) rats, between conditions of nicotine dose. Nicotine dose conditions are signified by the fill-color and dash-pattern of connecting lines. Each dose condition was tested twice under each FR schedule.

Figure 2.

Mean locomotor activity counts (±1 SEM) as a function of fixed-ratio (FR) schedule, in the female (left panel) and male (right panel) rats, between conditions of nicotine dose. Nicotine dose conditions are signified by the fill-color and dash-pattern of connecting lines. Each dose condition was tested twice under each FR schedule.

Figure 3.

Fits of the reinforcer demand model (lines) to the observed reinforcer consumption data (points) as fit to the group-averaged consumption data in the female (top panel) and male (bottom panel) rats. These curves are presented for representation purposes only, and for sake of clarity in presentation, curves for 0.05 and 0.2 mg/kg nicotine are not displayed (these are well characterized by 0.1 mg/kg in each sex). For actual analysis purposes, the reinforcer demand model was fit to the consumption data under each drug condition for each individual rat, yielding 100 separate fits of the demand model (mean R² = 0.905). Unit cost represents the response requirement per one dipper per kilogram bodyweight. Note the logarithmic scales of the y- and x-axes.

Figure 4.

Mean estimates (±1 SEM) of the ordinate intercept (Q₀) generated by fits of the reinforcer demand model to the consumption data of individual rats, displayed as a function of nicotine dose. Data from the males is displayed using closed circles and a solid line; data from the females is displayed using open circles and a dashed line. Points are offset for improved readability.

Figure 5.

Mean estimates (±1 SEM) of essential value (EV) generated by fits of the reinforcer demand model to the consumption data of individual rats, displayed as a function of nicotine dose. Data from the males are displayed using closed circles and a solid line; data from the females are displayed using open circles and a dashed line. Points are offset for improved readability.