These results are preliminary, but they suggest that characteristics broadly related to impulsivity, especially novelty seeking and response disinhibition, are associated with initial sensitivity to some effects of acute nicotine, including reinforcement and reward, and may do so differentially between men and women.

Initial sensitivity to nicotine's effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N=131). Participants engaged in 4 sessions, the first 3 to assess the dose-response effects of nasal spray nicotine (0, 5, 10 μg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some selfreported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 μg/kg) was administered via nasal spray followed by mood, nicotine reward (e.g. "liking") and perception (e.g. "feel effects") measures, physiological responses, sensory processing (pre-pulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine vs. placebo spray choice procedure. For the dopamine D4 receptor (DRD4 VNTR), presence of the 7 repeat allele was associated with greater aversive responses to nicotine (decreases in "vigor", positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased "feel effects" and greater startle response, but in men only. Also observed in men but not women were other genetic associations, such as greater "feel effects" and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T SNP) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G SNP (OPRM1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function Lerman has served as a consultant, and has received research funding unrelated to the present work, from Pfizer, GlaxoSmithKline, and AstraZeneca. Dr Benowitz has been a paid consultant to a number of pharmaceutical companies that market or are developing medications for smoking cessation. He has also been a paid expert witness in litigation against the tobacco industry in issues related to nicotine addiction. in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine prior to the onset of dependence and may do so differentially between men and women. NIH Public Access

Introduction: Research has identifi ed at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer.Methods: Lever pressing for a visual reinforcer under a fi xed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg).Results: Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a signifi cant decline in active responding. Conclusions:The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotinenaive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use.

Greater sensitivity to early exposure to tobacco smoking may predict higher risk of becoming nicotine dependent. The most common measure of this sensitivity is the retrospective self-report Early Smoking Experiences (ESE) questionnaire. We examined the relationship between responses to the retrospective ESE and prospectively assessed sensitivity to nicotine via nasal spray in young adult nonsmokers (N = 58) with modest lifetime smoking experience (>0 but < or =10 lifetime uses). Nicotine spray (0 vs 10 microg/kg) was used due to ethical and practical concerns with administering tobacco smoke to nonsmokers. Responses to cigarette smoking on the retrospective ESE items of pleasant, unpleasant, nausea, relaxed, dizzy, and buzzed were compared with prospectively assessed nicotine spray effects (NSE) on the same responses. ESE responses were also compared with subjective spray ratings of nicotine reward (e.g., "liking") and perception (e.g., "feel the effects"), cardiovascular activity, and nicotine reinforcement via a nicotine spray choice procedure. Results showed that the retrospective ESE items of dizzy and buzzed were each associated with greater prospective NSE dizzy and buzzed responses to nasal spray nicotine. However, the other four ESE items were unrelated to the corresponding NSE items. Responses to some ESE items were also related to prospective nicotine spray reward and perception, but no ESE item was related to the cardiovascular or reinforcing effects of nicotine spray. These findings show that two of six retrospective ESE items, dizzy and buzzed, predicted the same prospectively assessed responses to acute nicotine via spray in young adult nonsmokers and may reflect a stable and reliable response to nicotine intake.