Nicotinic Receptor Availability in Slow and Fast Nicotine Metabolizers
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Change in α4β2* nAChR binding potential
研究概览
简要总结
This positron emission tomography (PET) study examines the effects of 24 hours abstinence from smoking on return to availability of neuronal nicotinic receptors in slow and fast metabolizers of nicotine.
详细描述
The nicotine metabolite ratio (NMR), a stable marker of nicotine clearance rate, is a robust predictor of smoking relapse. Individuals who are fast nicotine metabolizers have higher rates of relapse, compared to slow metabolizers, on nicotine replacement or placebo treatment. Nicotine exerts its reinforcing properties, in part, by binding to α4β2* nicotinic acetylcholine receptors (nAChRs) in the brain. The α4β2* nAChRs are abundant and have high affinity for nicotine relative to other nAChR subtypes. The goal of this project is to identify abstinence-induced changes in neuronal nicotinic receptor availability that may underlie risk for smoking relapse.
The investigators propose to utilize positron emission tomography (PET) imaging to examine the association of variation in nicotine metabolism with return to availability of α4β2* nAChRs during early abstinence. The investigators will measure α4β2* receptor availability using the PET radio-ligand 2-[18F]FA, administered with bolus injection, on two separate occasions: during smoking as usual and after 24 hours of abstinence. The proposed study will help us understand the neurochemical mechanisms that underlie the higher risk of relapse among faster nicotine metabolizers, thereby pointing to potential targets for tailored therapy for these smokers at increased risk.
In addition, the investigators will invite six subjects who have completed the two PET scans described above to complete a third PET scan. During this third PET scan, the investigators plan to measure α4β2* receptor availability using the PET radio-ligand 2-[18F]FA, administered as bolus plus constant infusion after 24 hours of abstinence. The purpose will be to compare α4β2* nAChR binding potential data from the bolus 2-[18F]FA infusion protocol used in the main study to the bolus plus constant infusion protocol used in this third PET scan.
The protocol of this third PET scan will help the investigators demonstrate the feasibility at the University of Pennsylvania of administering the radiotracer as a bolus plus constant infusion, and the feasibility of scanning for two hours (versus one hour in the current protocol) paradigm. This data is important pilot data for future NIH grant submissions using this radiotracer.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ages 18 to 65 years old.
- •Smoke 10 cigarettes per day for the previous 6 months.
- •Weigh less than 300lbs (due to limitations of the PET and MRI scanners).
排除标准
- •Smoking behavior:
- •Current enrollment or plans to enroll in a smoking cessation program, or use other smoking cessation medications in the next 2 months.
- •Provide a CO reading of less than 10 ppm at medical screening.
- •Alcohol/Drugs:
- •History of substance abuse and/or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants).
- •Positive drug screen at any of the sessions (see page 8 for list of drugs and/or contra-indicated medications).
- •Current alcohol consumption that exceeds 25 standard drinks/week.
- •Providing a breath alcohol concentration (BrAC) reading of greater than or equal to 0.01 at any session.
- •Women who are pregnant, planning a pregnancy, or lactating; all female subjects shall undergo a serum pregnancy test at the medical screening session and urine pregnancy tests at the two PET scans and MRI scan.
- •Women of child-bearing age must agree in writing to use an approved method of contraception or agree to abstain from sexual intercourse
- •History or current diagnosis of the following psychiatric diagnoses identified by the MINI (Mini International Neuropsychiatric Interview) such as psychosis, bipolar disorder, schizophrenia, major current depression, or any Axis 1 disorder
- •Self-report of serious or unstable disease within the past 6 months (e.g., cancer [except melanoma], HIV/AIDS, stroke, angina, coronary disease, heart attack).
- •History of epilepsy or a seizure disorder.
- •Any medical or neurological condition that might interfere with the distribution of the radiotracer as determined by the study M.D.
- •Medication:
- •a. Current use or recent discontinuation (within last 14-days) of the following medications:
- •Any form of smoking cessation medication (Zyban, Wellbutrin, Wellbutrin SR, Chantix, NRT);
- •Recent (within last 14 days) or planned use of psychotropic medications (anti-psychotics, anti-depressants, anti-anxiety, anti-panic medications, mood stabilizers, opioids, and stimulants).
- •Participants shall be instructed to refrain from using any study prohibited drugs (note - participants are allowed to take prescription medicines not in the exclusion list) throughout their participation in the study.
- •Imaging-Related Exclusion Criteria:
- •Self-reported history of head trauma or brain (or CNS) tumor.
- •Self-reported history of claustrophobia (contraindicated for PET and MRI).
- •Having a cochlear implant or wearing bilateral hearing aids.
- •Self-reported use of pacemakers, certain metallic implants, or presence of metal in the eye as contraindicated for MRI.
- •History of gunshot wound.
- •Circumstances or conditions that may interfere with magnetic resonance imaging (MRI)
- •Inability to complete the baseline study procedures within four hours and/or correctly, as determined by the PI.
研究组 & 干预措施
NMR by abstinence status
This study uses a mixed design with one between-subject factor (NMR: continuous variable) and one within-subject factor (session: 24 hours abstinent vs. smoking as usual) to examine NMR by abstinence status interactions on α4β2* nAChR availability using 2-[18F]-fluro-3-[2(S)-2-azethidinylmethoxy]-pyridine (2-[18F]FA) PET imaging.
Subjects will participate in two one-hour PET sessions: a) after smoking as usual (smoking exposure standardized) and b) the other following 24 hours of smoking abstinence.
All participants who complete both PET scans will also complete an anatomical MRI scan.
干预措施: 2-[18F]-fluro-3-[2(S)-2-azethidinylmethoxy]-pyridine (Drug)
结局指标
主要结局
Change in α4β2* nAChR binding potential
时间窗: Week 1 and up to Week 5
This study uses a mixed design. A within-subject positron emission tomography (PET) study comparing α4β2\* nAChR availability, using 2-\[18F\]FA PET imaging, at two timepoints (1) during smoking as usual; and (2) after 24 hours of overnight abstinence. The order of the PET scans will be counterbalanced across subjects to prevent order effects that could bias the study results. Nicotine metabolite ratio (NMR) serves as the between-subject factor. The minimum amount of time between scans will be separated by one week. The maximum amount of time allowable between scans will be 4 weeks.
次要结局
- Behavioral Performance on cognitive tasks(Week 1 and up to Week 5)
- Cigarette craving(Week 0, Week 1, and up to Week 5)