We have developed a novel human laboratory model to examine two primary aspects of stress-precipitated tobacco relapse: 1) Does stress reduce the ability to resist the first cigarette? 2) Once the first cigarette is initiated, does stress facilitate subsequent smoking? Using a within-subject design, daily smokers (n=37) who were nicotine deprived overnight received a personalized imagery induction (stress or neutral) on two separate days, and then had the option of initiating a tobacco self-administration session or delaying initiation for up to 50 minutes in exchange for three levels of monetary reinforcement. Subsequently, the tobacco self-administration session entailed a 1-hour period in which subjects could choose to smoke using a smoking topography system. Following the stress induction, subjects were less able to resist smoking, smoked more intensely (increased puffs, shorter inter-puff interval, and greater peak puff velocity), and perceived greater satisfaction and reward from smoking. Stress significantly increased hypothalamus-pituitary-adrenal (HPA) axis reactivity, tobacco craving, negative emotion, and physiologic reactivity relative to the neutral condition. Additionally, increased cortisol, ACTH, and tobacco craving were associated with reduced ability to resist smoking following stress. These findings have implications for understanding the impact of stress on smoking relapse and model development to assess smoking lapse behavior.

Rationale Long-term smoking can lead to changes in autonomic function, including decreased vagal tone and altered stress responses. One index of the inability to adapt to stress may be blunted vagal reactivity. Stress is a primary mechanism involved in relapse to smoking, but mechanisms leading to stress-precipitated relapse are not well understood. Objectives Using an experimental paradigm of stress-precipitated smoking behavior, we examined whether autonomic reactivity mediates the relationship between stress and smoking. High-frequency heart rate variability (HF-HRV), a putative measure of vagal tone and the ratio of low-to-high frequency HRV (LF/HF), a measure of sympathovagal balance were assessed. Methods Using a within-subjects design, 32 nicotine dependent 15-hour abstinent smokers (a subgroup from McKee et al. (2011)) were exposed to individualized script-driven imagery of stressful and relaxing scenarios and assessed on the ability to resist smoking and subsequent ad-lib smoking. HRV was monitored throughout each laboratory session (maximum 60 min following imagery). Results As expected, stress and ad-lib smoking additively decreased HF-HRV and increased LF/HF. Blunted stress-induced HF-HRV responses reflecting decreased vagal reactivity were associated with less time to initiate smoking and increased craving relief and reinforcement from smoking. These relationships were specific to HF-HRV following stress as neither baseline HF-HRV, HF-HRV following relaxing imagery, or LF/HF predicted smoking behavior. Conclusions The current findings are the first to experimentally demonstrate that stress-precipitated decreased vagal reactivity predicts the ability to resist smoking. Findings suggest that strategies that normalize vagal reactivity in early abstinent smokers may lead to improved smoking cessation outcomes.

Preclinical findings support a role for α1-adrenergic antagonists in reducing nicotine motivated behaviors, but these findings have yet to be translated to humans. The current study evaluated whether doxazosin would attenuate stress-precipitated smoking in the human laboratory. Using a well-validated laboratory analogue of smoking-lapse behavior, this pilot study evaluated whether doxazosin (4 and 8 mg/day) versus placebo attenuated the effect of stress (vs. neutral imagery) on tobacco craving, the ability to resist smoking and subsequent ad-libitum smoking in nicotine-deprived smokers (n=35). Cortisol, adrenocorticotropin (ACTH), norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day versus placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day versus placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day versus placebo) further decreased tobacco craving following stress versus neutral imagery. Doxazosin increased the latency to start smoking following stress, and reduced the number of cigarettes smoked. Dosage of 8 mg/day doxazosin increased or normalized cortisol levels following stress imagery and decreased cortisol levels following neutral imagery. These preliminary findings support a role for the noradrenergic system in stress-precipitated smoking behavior, and support further development of doxazosin as a novel pharmacotherapeutic treatment strategy for smoking cessation.

Findings suggest that gender, dual diagnosis status, age and education may be an important predictors of aftercare treatment adherence and that gender may be a moderator of motivational interviewing among individuals with psychiatric disorders or dual diagnosis.

Guanfacine, a noradrenergic alpha2a agonist, reduced tobacco smoking in a 4-week trial and in animal models has been shown to reduce cortical dopamine release, which is critically involved in the reinforcing effect of tobacco smoking. We measured amphetamine-induced extrastriatal dopamine release before and after treatment with guanfacine with [C]FLB457, a dopamine D/D receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [C]FLB457 PET scans on the same day, one before and one at 2.5-3 h after amphetamine (0.4-0.5 mg/kg, PO). A subset (n=12) then underwent guanfacine treatment (3 mg/day for 3 weeks) and the set of scans were repeated. [C]FLB457-binding potential (BP) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BP after vs before amphetamine (Δ BP) is an indirect measure of DA release and was compared between the untreated and guanfacine-treated conditions. Guanfacine treatment attenuated amphetamine-induced DA release; however, the change was due to a global 8% decrease in baseline BP from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [C]FLB457 BP in tobacco smokers, suggesting an increase in dopaminergic tone. Guanfacine-induced normalization of dopamine signaling may be an important mesocortical mechanism contributing to its ability to aid in tobacco smoking cessation.