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Try out PMC Labs and tell us what you think. Learn More. Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose—response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects 12 male and 14 female participated in four experimental sessions in which they received sample infusions of saline and nicotine 0.
During each session, subjects first received the sample infusions, and heart rate HRblood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm.
Nicotine self-administration rate was negatively correlated with nicotine dose in males males displayed choice preference for low doses of nicotine over high doses of nicotinebut no ificant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects.
Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration. With the legislation that empowered the Food and Drug Administration to control tobacco products, reducing the addiction potential and harmful effects of cigarette smoking became a more achievable goal.
Benowitz and Henningfield proposed that the gradual reduction of the nicotine content of cigarettes to an amount below the addictive threshold could prevent the development of addiction among young smokers who are experimenting with cigarettes Benowitz and Henningfield, They further predicted that nicotine doses below this threshold would not be reinforcing or able to maintain nicotine addiction. The dose—response function for nicotine reinforcement, however, has yet to be empirically examined by carefully controlled studies in humans.
Intravenous IV self-administration models are the gold standard for assessing the reinforcing effects of drugs of abuse, including nicotine. Henningfield and colleagues pioneered IV nicotine self-administration NSA procedures in humans Harvey et al; Henningfield and Goldberg, a ; Henningfield et alb.
In a study of male and female smokers, we examined self-administration of IV nicotine using a choice procedure in which smokers were able to choose between three IV nicotine doses and saline. In that study, we used single nicotine doses 0. We found that both 0. However, many questions remain for NSA in humans, including the generation of a reliable estimate for the threshold dose for reinforcement, as well as a dose—response curve for reinforcement.
In animal models Corrigall et al; Donny et al; Fattore et al; Le Foll et al; Rose and Corrigall,the dose-dependent changes in nicotine reinforcement are restricted to low- and high-dose ends of the dose—response curve, whereas the middle range is relatively insensitive to changes in nicotine doses Rose and Corrigall, It is unknown whether a similar NSA pattern exists in humans as well. The purpose of this study was to characterize the dose—response curve for IV NSA in male and female smokers, which has not been examined in human studies.
To reach this goal, we used a NSA model that included nicotine doses of 0. We hypothesized that this range of nicotine doses would be near the threshold dose for reinforcement. In addition to self-administration, we also collected measures of heart rate HRblood pressure, and positive and negative subjective ratings of drug effects. The subjects were non-treatment seeking, dependent smokers recruited from the New Haven, CT area.
Demographic variables and cigarette smoking history for males and females are shown in Table 1. Twelve male and 14 female subjects participated in all four sessions; 6 subjects were removed from all analyses because they were not compliant with study procedures or they opted out voluntarily before study completion. All participants had normal physical, laboratory, and psychiatric examinations, and participants had no current drug abuse or dependence for any substances other than nicotine, as established by the structured clinical interview for DSM-IV American Psychological Association, A urine drug screening before each session was performed to assess for recent exclusionary drug use opiates, phencyclidine, cocaine, amphetamines, and benzodiazepines.
Each participant gave a ed informed consent before the study participation. This outpatient, double-blind, crossover study had four experimental sessions. At the start of each session, an indwelling IV catheter was inserted in the subject's antecubital vein for nicotine infusion, blood drawing, and as a safety precaution.
Each experimental session consisted of one randomly ased nicotine dose 0. At the start of each session, subjects first sampled their ased nicotine dose either 0. Cardiac rhythm was monitored continuously during sessions, and lead ECGs were obtained before and at the end of the session. Nicotine stock solution vials were prepared by dissolving nicotine bitartrate dihydrate powder in 0.
The amount of nicotine bitartrate dihydrate powder was adjusted by molecular weight to reflect nicotine free base. Each batch of nicotine solution was tested for pyrogenicity, sterility, and analyzed by quantitative assay, which yielded satisfactory in all cases. An investigational new drug application was obtained from the Food and Drug Administration for IV nicotine. The syringe that contained the nicotine dose had enough volume to for the line flush and seven experimental infusions, one for the sample dose and the six optional doses for the choice trials.
The nine items were grouped into three domains based on prior work showing high correlations between DEQ responses Jensen et alab ; Morean et al Forced-choice preference and dose discrimination were evaluated using Generalized Estimating Equations Zeger et al, with a negative binomial distribution for the of times a participant chose nicotine in a session, and a log link and exchangeable working correlation structure across sessions within individuals.
We tested the effects of sex, nicotine dose, and sex by nicotine dose, and controlled for consecutive session and drug administration order. One subject male failed to complete the sixth forced-choice trial of the 0. This subject had selected nicotine for five of five forced-choice trials, and including the data with either a selection of nicotine or saline for the final forced-choice trial yielded no material change to the.
The main and interactive effects of sex were tested in all models for cardiovascular effects and subjective effects. Cardiovascular effects were assessed using linear mixed effects models with SBP, DBP, and HR considered separately as response variables, sex as a between-subject factor, nicotine dose, drug nicotine vs placeboand time all repeated measurements within each treatment on each test day as within-subject factors, and all possible interactions.
Period and sequence effects were controlled for by including test day and order of drug administration on each test day nicotine first or placebo first as additional predictors in the models. Two-way interactions between test day and order, and between drug and order were considered, but dropped from the models because they were not ificant. Random effects for subject, test day within subject, and drug within test day and within subject were used to for correlations between repeated measures. Post hoc tests were performed in order to explain ificant interactions.
ificance level of 0. Because of the skewed distributions of the subjective effects data, nonparametric analyses were performed. We used the nonparametric approach of Brunner et al for repeated measures data with stimulatory, pleasurable, and aversive effects considered separately as response variables. The raw subject effects data were converted into ranks first and then were entered into a mixed model with sex as a between-subject factor, nicotine dose, drug nicotine vs placebo and time all repeated measures as within-subject factors, and subject as the clustering factor.
All interactions were tested in the model, and we controlled for period and sequence effects by including main effects and interactions of day and infusion order, and of infusion order and drug. Non-ificant interactions involving day and infusion order were dropped from the final models. The variance—covariance structure was unconstrained. Contrasts were used to explain any ificant interactions or main effects.
The overall alpha level for each scale was fixed at 0. At the 0. Males chose to self-administer nicotine over saline more often at 0. In contrast, among females there were no between-dose differences in choice preference for nicotine over saline across nicotine doses Figure 1. The responses at each forced-choice option for males and females are shown in Figure 2. Sex differences in intravenous IV nicotine self-administration.
In males, 0. Intravenous nicotine self-administration frequency for each forced-choice trial. The ing indicates the forced-choice trial, 1—6. All nicotine doses 0. The between-dose increases in ratings of pleasurable effects were subtle and not supported statistically.
These interactions indicated that the ratings of stimulatory effects were higher relative to saline at doses of 0. Figure 4 shows the average saline-normalized subjective ratings for stimulatory, pleasurable, and aversive effects following nicotine treatment for male and female subjects grouped separately.
Supplementary Figure S1 shows the subjective ratings for stimulatory, pleasurable, and aversive effects in response to saline and nicotine at all time points for male and female subjects grouped separately. There were no ificant effects involving sex.
The average aversive rating following 0. Dose sensitive differences in the subjective ratings of intravenous nicotine. Responses are grouped horizontally by escalating nicotine dose 0. The subjective rating of intravenous nicotine among male and female smokers. The subjective ratings for nicotine are relative to the ratings for saline, using the Drug Effects Questionnaire with a scale of 0— HR showed an interaction between nicotine dose and drug F 3, SBP responded to nicotine dose F 3, In males, DBP was ificantly higher at 0. Supplementary Figure S2 shows the cardiovascular response to saline and nicotine at all time points for male and female subjects grouped separately.
There was no discernable influence of sex on the effect of 0. The acute cardiovascular effects of intravenous IV nicotine at low doses. The purpose of this study was to characterize the dose—response function for IV NSA in male and female smokers. Precise doses of nicotine were administered to smokers by IV infusion at concentrations that an individual might experience while puffing on a typical tobacco cigarette 0.
Among males, low doses of IV nicotine were preferentially chosen over high doses of nicotine. In contrast, among females no choice preference was observed. The IV nicotine doses also induced subjective ratings of positive and negative drug effects that differed from saline. Notably, all doses tested, including the lowest tested dose 0. The dose-dependent sex differences in reinforcement behavior and the dose-dependent changes in positive and negative subjective ratings of drug effects are relevant to dependence vulnerability.Nsa smoke and sex
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