Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior.

INTRODUCTION: Separate α1- and ß-adrenergic antagonists have shown efficacy in reducing nicotine-motivated behaviors in rodents and humans, supporting a role for the noradrenergic system in mediating the reinforcing properties of drugs of abuse. However, the effect of the combined α1- and ß-adrenergic antagonist, carvedilol, on stress-related smoking is unknown. METHODS: Using a well-established human laboratory model of stress-precipitated smoking-lapse behavior, we examined whether carvedilol (0 or 50 mg/day; between subject, n=17 per group), administered to steady-state, would attenuate the ability to resist smoking following stress imagery (vs. neutral imagery) and reduce subsequent smoking self-administration in nicotine-deprived smokers ( n = 34 total). Tobacco craving, withdrawal, and physiologic reactivity were also assessed. RESULTS: Latency to start smoking and number of cigarettes smoked during the self-administration period did not differ by medication condition. Counter to our hypothesis, tobacco craving demonstrated a medication × time effect, with greater craving in the carvedilol condition. Systolic blood pressure and heart rate demonstrated lower values in the carvedilol versus placebo group, consistent with known effects of carvedilol. CONCLUSION: While carvedilol attenuated physiologic reactivity consistent with its clinical indication, beneficial effects on smoking outcomes were absent in this preliminary investigation and may suggest possible worsening. Future work may benefit from discerning the single versus combined effects of α1- and ß-adrenergic antagonism on smoking outcomes.

The Effect of Treatment with Guanfacine, an Alpha2 Adrenergic Agonist, on Dopaminergic Tone in Tobacco Smokers: An [11C]FLB457 PET Study.

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 [11C]FLB457, a dopamine D2/D3 receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [11C]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. [11C]FLB457-binding potential (BPND) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BPND after vs before amphetamine (Δ BPND) 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 BPND from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [11C]FLB457 BPND 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.

Effect of doxazosin on stress reactivity and the ability to resist smoking.

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, norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day vs placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day vs placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day vs 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.

Predictors and moderators of aftercare appointment-keeping following brief motivational interviewing among patients with psychiatric disorders or dual diagnosis.

OBJECTIVE: Non-adherence to psychiatric and substance abuse treatment recommendations, especially with regard to aftercare outpatient appointment-keeping following hospitalizations, exacts a high cost on mental health spending and prevents patients from receiving therapeutic doses of treatment. Our primary objective was to evaluate the relationship between potential predictors and moderators of aftercare appointment-keeping among a group of adult patients immediately following hospitalization for severe psychiatric disorders or dual diagnosis. METHODS: Candidate predictors and moderator variables included demographics, psychiatric status, psychiatric symptom severity, and inpatient group adherence, while aftercare appointment-keeping was defined as attendance at the first aftercare appointment. Participants were 121 adult inpatients with a psychiatric disorder or dual diagnosis originally enrolled in an earlier randomized controlled trial comparing standard treatment with standard treatment plus brief motivational interviewing for increasing adherence. RESULTS: RESULTS indicated that, across treatment conditions, those who were female, did not have dual diagnosis, were older (older than 33 years), and were less educated (

Blunted vagal reactivity predicts stress-precipitated tobacco smoking.

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-h abstinent smokers (a subgroup from McKee et al. (J Psychopharmacol 25(4):490-502, 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.

Stress decreases the ability to resist smoking and potentiates smoking intensity and reward.

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 min 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. In addition, 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.

Research- and community-based clinicians' attitudes on treatment manuals.

We assessed the attitudes of 18 research- and 22 community-based substance abuse clinicians on treatment manuals. Research and community clinicians exhibited favorable attitudes toward manuals, and the majority (72% and 77%, respectively) reported an interest in learning more about substance use disorder (SUD) treatment manuals. Among community clinicians, greater years of experience was significantly associated with less favorable attitudes toward treatment manuals. Research clinicians endorsed significantly higher ratings for the importance attached to "theoretical rationale/overview" and "main session points to address" than community clinicians. Findings suggest that community SUD clinicians are already familiar with and have positive attitudes toward manuals, but specific subgroups have concerns that should be addressed.