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.

Assessment of ethanol and nicotine interactions using a reinforcer demand modeling with grouped and individual levels of analyses in a long-access self-administration model using male rats

“…It is important to point out that there was a significant difference in the effect of contingent "lowcost" and contingent "high-cost" nicotine availability on the responding for ethanol because only when nicotine was available on the FR1 schedule of reinforcement the consumption of the ethanol increased (see Figure 5A). Overall, these findings support a body of literature showing that nicotine increases the reinforcing value of ethanol (Barrett et al, 2020;Doyon et al, 2013;Lallemand et al, 2007;Lárraga et al, 2017;Marshall et al, 2003;Smith et al, 1999) with additional refinement of our understanding of roles of nicotine contingency and "cost" in the interaction effects with ethanol. Our interaction tests also showed that contingent "low-cost" ethanol significantly decreased responding for nicotine on a progressive schedule of reinforcement while noncontingent nicotine or continent "high-cost" nicotine availability had no effect (Figure 5B).…”

“…Some of the variability in the preclinical studies likely stems from variability in methodological approaches to sample relevant data. For example, some studies rely on noncontingent (bottle or vapor) ethanol delivery (Chandler et al, 2020; Lallemand et al, 2007; Marshall et al, 2003; Potthoff et al, 1983; Smith et al, 1999), while others utilize contingent operant protocols for ethanol self-administration (Barrett et al, 2020; Deehan et al, 2015; Doyon et al, 2013; Lárraga et al, 2017). Likewise, nicotine administration in those previous studies also varied with nicotine consumed noncontingently through drinking solutions (Lallemand et al, 2007; Marshall et al, 2003; Potthoff et al, 1983), contingently through drinking solutions (Deehan et al, 2015), noncontingently using systemic injections (Barrett et al, 2020; Doyon et al, 2013; Smith et al, 1999), or contingently using intravenous self-administration protocols (Chandler et al, 2020; Lárraga et al, 2017).…”

Reward Responsiveness in the Adolescent Brain Cognitive Development (ABCD) Study: African Americans’ Diminished Returns of Parental Education

“…A higher reward responsiveness of males than females is known. This is also related to the higher impulsivity [ 127 , 128 , 129 , 130 , 131 ], reward dependence [ 16 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ], and novelty seeking [ 140 , 141 , 142 , 143 ] of males than females. The result is a higher risk taking of males than females [ 127 , 144 , 145 , 146 ].…”

Sex Differences in the Nicotinic Acetylcholine Receptor System of Rodents: Impacts on Nicotine and Alcohol Reward Behaviors

“…Similarly, a recent report used a reinforcer demand analysis in which Wistar rats that were trained to self-administer alcohol were first pretreated with nicotine followed by an exponential reinforcer demand method to measure the reinforcement index of alcohol following nicotine treatment. In this study, male rats displayed higher alcohol reinforcement at baseline, whereas low-to-moderate doses of nicotine increased perseverative responding for alcohol infusions only in females ( Barrett et al, 2020 ). These data suggest that female rodents may exhibit unique behavioral responses to co-consumption of alcohol and nicotine, which could have important consequences for treating comorbid alcohol and nicotine use disorders.…”

“…While the comorbidity of alcohol and nicotine use disorders has been widely studied in human patients, less research has been Barrett et al, 2020 bPiDi, N,N-decane-1,10-diyl-bis-3-picolinium diiodide; CPP, conditioned place preference; DID, drinking-in-the-dark; KO, knockout; LORR, loss of righting reflex; n.d., no difference.…”