Carolyn Fonte

Nasal spray nicotine replacement suppresses cigarette smoking desire and behavior

The effects of short‐term nasal spray nicotine replacement in suppressing desire to smoke and ad libitum cigarette smoking behavior were evaluated in male and female smokers. In study I, 10 male and 10 female smokers received intermittent doses of 0, 7.5, 15, and 30 µg/kg nicotine by way of measured‐dose nasal spray, with each dose on a separate day. Self‐reported desire to smoke was significantly suppressed by each nicotine dose compared with placebo, but there were no significant differences among nicotine doses or between men and women. In study II, eight male and eight female smokers received 0, 15, and 30 µg/kg nicotine intermittently and were allowed to smoke their preferred brands of cigarettes ad libitum. Similar to study I, nicotine replacement significantly suppressed number of cigarettes smoked, number of puffs, and carbon monoxide boost and increased latency to smoking, but there were almost no significant differences between the two nicotine doses. Magnitude of smoking suppression attributable to 15 µg/kg tended to be greater in men than in women. However, plasma nicotine concentrations were significantly higher after 15 and 30 µg/kg versus placebo, suggesting only partial compensation in smoking behavior with short‐term nasal nicotine replacement. These findings support the idea that short‐term nicotine replacement decreases smoking desire and behavior, but the findings indicate that smoking behavior is partly influenced by factors other than nicotine regulation.

Nicotine preference in smokers as a function of smoking abstinence.

Overnight smoking abstinence increases desire to smoke and intensity of smoking behavior in smokers, but it is not completely clear that this reflects an increase in reinforcement from the psychoactive effects of nicotine per se. We examined choice of nicotine vs. placebo via nasal spray (Study 1) and nicotine vs. nonnicotine cigarette puffs (Study 2) in separate groups of smokers during each of two sessions, following overnight abstinence vs. no abstinence. In each study, subjects followed a forced choice procedure in which they were instructed to self-administer six sprays/puffs from between the two nasal sprays/cigarettes every 15 min for 2 h following initial exposure to each. In Study 1, choice of nicotine spray (1.5 micrograms/kg per spray) increased significantly following abstinence vs. no abstinence (47 +/- 6% vs. 34 +/- 5%, respectively, p < 0.05). This shift in choice was more pronounced in the subset of smokers (choosers, n = 9 out of 24) who selected nicotine on more than 50% of choices on the abstinent day. Choosers exhibited greater responses to initial nicotine exposure on positive (e.g., pleasant, vigor) but not aversive (e.g., jittery, uneasy) subjective measures, suggesting that greater positive reinforcement from nicotine per se predicted subsequent choice. In Study 2, abstinence similarly increased choice of nicotine vs. nonnicotine cigarette puffs (82 +/- 6% vs. 64 +/- 8%, p < 0.05), although nearly all subjects (12 of 13) preferred the nicotine cigarette following abstinence. These results indicate that choice of nicotine per se, isolated from tobacco smoke, increases significantly after overnight tobacco abstinence.

Subjective and cardiovascular responses to nicotine combined with caffeine during rest and casual activity

Although nicotine and caffeine have separately been shown to acutely increase subjective arousal, their combined effects are unclear. Furthermore, their effects during casual physical activity, the condition under which individuals usually experience nicotine and caffeine, are unknown. Smokers who were regular coffee drinkers (n=19, 9 males, 10 females) participated in eight morning sessions, involving nicotine/placebo, caffeine/no caffeine, and rest/physical activity (i.e. 2×2×2 within-subjects design). Nicotine (15 µg/kg) or placebo was given via measured-dose nasal spray intermittently after consumption of decaf coffee with or without added caffeine (5 mg/kg), followed by subjective [Profile of Mood States (POMS), Stress-Arousal Checklist, visual analog scales] and cardiovascular (heart rate, blood pressure) measures. Casual physical activity was standardized by low-intensity bicycle riding while sitting comfortably. Results indicated significant subjective and cardiovascular effects of nicotine and caffeine individually, with the combination of nicotine and caffeine generally producing additive or greater than additive effects for each measure. However, activity mediated some of the subjective effects of nicotine, as nicotine appeared to be “stimulating” during rest but not during activity. There were no differences between males and females. These findings suggest that nicotine per se and caffeine generally have additive subjective and cardiovascular effects, and that nicotine may influence subjective stimulation differentially depending on whether a smoker is resting or engaged in casual activity.

Effects of central and peripheral nicotinic blockade on human nicotine discrimination

Abstract Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg PO), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10–40 μg/kg per min IV), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 μg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 μg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects.

Effects of smoking status and smoking cessation on leptin levels

Cigarette smoking is associated with lower body weight, and quitting smoking typically produces weight gain. An effect of chronic smoking on increasing leptin, a protein product associated with reducing weight, may help explain this influence of smoking on lowering body weight. We examined fasting serum leptin levels in male and female adult smokers (n = 52) and non-smokers (n = 12) as well as long-time ex-smokers (n = 13), with all groups similar in body mass index (BMI). Partial regression analyses controlling for BMI and, where relevant, age were used to relate leptin to indices of smoking exposure and dependence within the smokers, and with typical alcohol and caffeine intake in the entire sample. Furthermore, a subset of the smokers (n = 22) quit for at least 3 weeks, and changes in leptin and weight were prospectively assessed. Results showed no difference in mean leptin levels as a function of smoking status and no significant associations of leptin with smoking exposure variables after controlling for BMI and age. However, leptin was significantly correlated with alcohol intake (inversely) in women. In addition, smoking cessation increased leptin, the opposite change expected if leptin were responsible for weight gain, but again only in women and not in men. This leptin change remained significant after controlling for the increase in weight observed in both men and women. In conclusion, the influence of cigarette smoking on body weight does not appear to be due directly to changes in leptin levels, as there is no difference in leptin due to smoking status and leptin does not decline after cessation.

Gender, dietary restraint, and smoking's influence on hunger and the reinforcing value of food

Smoking may enhance satiety following meal consumption, thereby reducing subsequent eating (i.e., between-meal snacks), especially in women high in dietary restraint. Female smokers (n = 20, 10 high and 10 low restraint) and male smokers (n = 10) participated in two sessions, involving overnight abstinence from food and smoking (smoking abstinence day) or from food only (smoking day), in a within-subjects design. The reinforcing value of food was determined by the number of responses made to obtain food reinforcers (100-kcal snack portions) vs. money using a concurrent schedules computer task. Subjects were given a small caloric load on each day followed by access to food vs. money. On the smoking day, subjects were allowed to smoke every 30 min during the session as well as ad lib before the session. Self-reported hunger was also assessed upon arrival (after fasting) and following the caloric load during each session. Results indicated no effect of smoking on initial hunger rating, after fasting, but hunger ratings following the caloric load declined significantly more during smoking vs. abstinence days for all subjects, consistent with an enhancement of postmeal satiety due to smoking. There was no overall main effect of smoking on food-reinforced responding. However, responding for food was significantly less during the smoking vs. abstinence days for high-restraint females only and not for low-restraint females or for males. These findings indicate that smokings acute influence on reducing food intake does not reflect a broad gender difference but may be specific to dietary restraint.

Sex differences in the acute effects of cigarette smoking on the reinforcing value of alcohol.

Alcohol consumption acutely increases smoking behavior, but the reverse relationship, the acute effects of smoking on alcohol intake, largely has been ignored. We examined whether smoking acutely increases the reinforcing value of alcohol, first in the absence of recent alcohol intake and then following an alcohol pre‐load. Healthy, social‐drinking smokers (n  = 11 men, 14 women) engaged in a computerized task involving concurrent schedules of reinforcement for beer (FR10, 3 oz (90 ml) per reinforcement) or money (FR5 to FR30,

Reinforcing effects of nicotine as a function of smoking status.

0.20 per reinforcement) during two sessions, one following day‐long ad lib smoking and the other following overnight smoking abstinence. During each session, subjects performed the task in two sets of trials, one before and one after consumption of an alcohol pre‐load, with 60 min between sets. To standardize the alcohol pre‐load, all subjects were led to believe that they had earned 9 oz (270 ml) of beer after the first trial set, which they then consumed before the second set of trials. Compared to responding during the abstinent session, responding for alcohol during the smoking session was no different before the alcohol pre‐load (trial set one) but was significantly greater following the alcohol pre‐load (trial set two), although only in men and not women. Subjective sedation after the alcohol pre‐load was attenuated during the smoking session in both men and women, but attenuated sedation due to smoking was related to subsequent alcohol‐reinforced responding only in men. Additional research is needed to determine the extent to which these effects in men are pharmacological in nature or are conditioned responses to smoking or to consuming a preferred alcoholic beverage.

Cross-validation of a new procedure for early screening of smoking cessation medications in humans.

The authors compared acute nicotine self-administration among 4 groups varying in current or past dependence: dependent smokers, nondependent smokers, ex-smokers who had quit at least 1 year ago, and nonsmokers. Nicotine (0 vs. 12 microg/kg/8 sprays) available by nasal spray was self-administered with a choice procedure. Self-administration also was related to participant characteristics (sex, alcohol and caffeine intake, sensation-seeking score) and to subjective responses to initial nicotine spray exposure. Nicotine self-administration was similar between dependent and nondependent smokers but was greater in those groups than in ex-smokers and nonsmokers, who did not differ from each other. Self-administration was unrelated to most other participant characteristics. In nonsmokers, self-administration was related directly to pleasurable effects but inversely to aversive effects. Few effects were related to self-administration in the other groups.

Nicotinic Acetylcholine Receptor β2 Subunit (CHRNB2) Gene and Short-Term Ability to Quit Smoking in Response to Nicotine Patch

Brief procedures for evaluating medication efficacy may reveal which candidate drugs warrant further testing in clinical trials and which do not. We previously carried out a study of smoking abstinence, involving the nicotine patch, and established the sensitivity of our procedure. In this study, we sought to cross‐validate our earlier work by comparing short‐term smoking abstinence due to varenicline (relative to placebo) in smokers with high intrinsic quit interest (n = 57) and those with low intrinsic quit interest (n = 67). All the subjects were randomly assigned to either abstinence reinforcement (