Investigation of Nicotine Seeking Behavior in Current Smokers

Study Overview
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Brief Summary
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In this study, 21 non-treatment-seeking cigarette smokers were recruited to investigate the effects of acute stress on brain function and nicotine seeking/self-administration behavior.

Detailed Description
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Non-treatment-seeking cigarette smoking individuals were recruited from the Detroit, MI area. Individuals were screened for cardiovascular, neurological, and psychiatric contraindications. 21 healthy smokers completed two oral pre-treatment experimental sessions (on separate non-consecutive days) in randomized order under double-blind conditions: placebo (lactose) and stress (54mg yohimbine and 10mg hydrocortisone). Yohimbine + hydrocortisone elicit a neurochemical and physiological response that mimics a 'natural' stressor. Placebo and stress sessions were identical and started at 11am. Upon arrival, subject sobriety was confirmed with expired breath alcohol measurement (<.02%). At 11:30am, each subject smoked 6 cigarette puffs (preferred brand; provided by study) over 5 minutes to control for recent nicotine exposure. Throughout each experimental session, subjects periodically completed self-reported measures of cigarette craving, nicotine withdrawal symptoms, affect, and anxiety, and vital signs were measured. Subjects self-administered (swallowed) oral doses of yohimbine (or placebo) at 11:45am and hydrocortisone (or placebo) at 12:15pm. At 1pm, subjects completed a 60-min neuroimaging scan which included: 1) T1-weighted structural scan, 2) proton functional magnetic resonance spectroscopy (fMRS) acquisition from the left prefrontal cortex during a letter 2-back working memory paradigm, and 3) functional magnetic resonance imaging (fMRI) acquisition during an N-back paradigm yoked with cigarette cues. At 2:30pm, subjects completed an 11-trial choice progressive ratio task in which they could earn cigarette puffs (preferred brand; provided by study) or money. At 3pm, subjects self-administered earned cigarette puffs (video monitored). Subjects remained on site until 4pm discharge.

Official Title
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Neuropharmacological Investigation of Frontostriatal Network Function and Nicotine Seeking Behavior in Current Smokers

Conditions
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Cigarette Smoking

Intervention / Treatment
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* Drug: Yohimbine Hydrochloride
* Drug: Hydrocortisone
* Drug: Lactose Monohydrate Powder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1) Aged between 21-35 years old, 2) current smokers (expired breath carbon monoxide > 4ppm, self-reported 10+ cigarettes/day, Fagerstrom test for nicotine dependence score > 3, 3) normal seated and resting vital signs (systolic blood pressure 80-160mmHg, diastolic blood pressure 50-90mmHg, and heart rate 50-90 bpm), and 4) normal or corrected-normal vision. Exclusion Criteria: 1) Abnormal electrocardiogram (reviewed by licensed cardiologist), 2) magnetic resonance imaging contraindications (e.g. metal implants), 3) medical/neurological contraindications (e.g., diabetes or head trauma), 4) pregnancy (urine test; females only), 5) positive urine test result for opioids, cocaine metabolites, benzodiazepines, barbiturates, or amphetamines, 6) psychiatric contraindications (subject met criteria for current Axis 1 disorder [other than nicotine dependence] as indicated by computerized MINI-6 screen), and 7) self-reported marijuana and/or alcohol use on 15+ days in the past month.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Double-blind, placebo-controlled, and randomized cross-over study design. Each subject completed both the placebo and acute stress experimental sessions.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>The placebo compound, Lactose Monohydrate Powder, was encapsulated in generic opaque capsules identical to the capsules used in the acute stress session. During the placebo session, two capsules were self-administered (swallowed) by each subject. At 11:45am, subjects self-administered a capsule containing 54mg of lactose. At 12:15pm, subjects self-administered a capsule containing 10mg of lactose. | Drug: Lactose Monohydrate Powder<br>* Lactose powder was encapsulated in generic opaque capsules identical to those used during the acute stress session. Lactose doses weighed the same as the acute stress session doses (54mg and 10mg, respectively).<br>* Other names: Placebo;|
| Experimental: Acute Stress<br>During the acute stress experimental session, subjects self-administered two generic opaque capsules. At 11:45am, subjects self-administered a capsule containing 54mg of Yohimbine Hydrochloride powder. At 12:15pm, subjects self-administered a capsule containing 10mg of Hydrocortisone. | Drug: Yohimbine Hydrochloride<br>* 54mg of yohimbine powder was encapsulated in a generic opaque capsule and swallowed with water.<br>* Other names: YOH;Drug: Hydrocortisone<br>* 10mg hydrocortisone was encapsulated in a generic opaque capsule and swallowed with water.<br>* Other names: HYD;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cigarette puff vs. money choice task | Participants could earn (via computer mouse 'clicks') money or cigarette puffs (preferred brand; provided by the study) across 11 independent choice trials. At the start of each trial, subjects selected either money or cigarette puffs on a computer screen. After each selection, subjects could earn one unit of that selection by satisfying the computer 'mouse' click requirement. The click requirement increased with each successive unit earned separately for cigarette puffs and money following a progressive ratio schedule (5, 12, 33, 100, 180, 340, 540, 835, 1220, 1660, and 2275 'mouse' clicks; identical schedule for both options and experimental sessions). Units were $0.25 money and 1 cigarette puff. Earned cigarette puffs were smoked at the end of the task and earned money was applied to the subject's study payment. The task was completed between 2:30pm and 3pm for each session. | 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Letter 2-back task | Participants completed 5 blocks of a letter 2-back working memory task during proton functional magnetic resonance spectroscopy data acquisition from the left dorsolateral prefrontal cortex. The 2-back task consisted of a neurochemistry normalization period (passive viewing of a 3Hz flashing checkerboard; 208s) and alternating periods of passive visual fixation (centered fixation cross; 32s) and letter 2-back (64s; 4s instructions ['2-back'], 20 letters [3s/letter; 500ms on screen; 2500ms blank screen], 6 target letters). Changes in neurochemistry as quantified using LCModel were the primary outcome variable. 2-back response accuracy (% correct) and response latency (ms) were secondary outcomes. | 12 minutes | 
| Cigarette-cued letter N-back task | Participants completed a neutral image vs. cigarette smoking-related image cued letter N-back task during functional magnetic resonance imaging acquisition. The task consisted of pseudo-randomly ordered blocks of 0-, 1-, and 2-back with either cigarette cues or matched neutral images behind each letter. Two 32s blocks of each task permutation were collected separated by 16s of blank screen (to minimize carry-over effects). Patterns of brain activation throughout the task was the primary outcome measure while N-back response accuracy (% correct) and response latency (ms) were secondary outcomes. | 15 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cigarette smoking, acute stress, executive function, craving, nicotine seeking, relapse, excitatory neural activity, glutamate, negative affect