Effects of Nicotine on Brain Opioid Receptors

A substantial body of evidence implicates the endogenous opioid system, and the mu opioid receptor (MOR) in particular, in the reinforcing effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the mu opioid receptor gene (OPRM1 Asp40) is associated with the ability to quit smoking, as well as nicotine reward and withdrawal symptoms. However, the precise mechanism through which this SNP influences nicotine dependence remains unresolved. This positron emission tomography (PET) study will examine whether this OPRM1 SNP alters MOR binding in response to nicotine in human smokers. Specifically, we will use \[11 C\]carfentanil PET imaging to assess the effects of intravenous (IV) nicotine versus saline (within-subject) on MOR binding potential in 24 chronic smokers genotyped prospectively and stratified by OPRM1 genotype.

The study uses a mixed factorial design with one between subject factor (OPRM1 genotype_: Asn40/Asn40 vs. Asn40/Asp40 or Asp40/Asp40) and one within-subject factor (IV nicotine vs. IV saline) to examine genotype by nicotine interactions on MOR binding potential (BP_ND ) assessed via PET imaging with \[11 C\]carfentanil. Twenty-four smokers (12 male, 12 female; 12 from each genotype group) will participate in two 90 minute PET sessions following overnight (14-hours) abstinence from nicotine. Genotype groups will be matched for age and sex . One week prior to the first PET session, there will be an adaptation session during which participants will receive IV saline followed 30 minutes later by IV nicotine (1 mg/70 kg) to ensure that they tolerate the procedure. In the PET sessions, participants will receive either IV nicotine (1 mg/70 kg) or saline (within-subject, double blind, counterbalanced). The primary outcomes will be BP_ND in ventral striatum and anterior cingulate cortex (ACC). Normally menstruating women will be scheduled for their sessions during the early follicular phase. Sessions will be separated by 1 month for all participants to reduce variability in MOR binding due to hormonal changes during females menstrual cycles. Participants will complete subjective measures of nicotine reward and craving at each session.

Eligibility Criteria:
Inclusion Criteria:

* Non-treatment seeking smokers of European ancestry
* Between 18 and 50 years old
* Smoking at least 10 cigarettes per day for at least the past 6 months
* Able to provide informed consent
* Fluent, English-speaking
* Weight ≤ 300 lbs.

Exclusion Criteria:

* Current enrollment or plans to enroll in a smoking cessation program, or use other smoking cessation medications in the next 2 months
* Provide a Carbon Monoxide reading of ≤10 ppm at Medical screening.
* History of substance abuse and/or currently receiving treatment for substance abuse (e.g., alcohol, opioids, cocaine, marijuana, or stimulants)
* Current alcohol consumption that exceeds 25 standard drinks/week
* Providing a breath alcohol concentration (BAC) reading of \> 0.01 at any session.
* Women who are pregnant, planning a pregnancy, or lactating; all female subjects shall undergo a urine pregnancy test at each session
* Women of child-bearing age must agree in writing to use an approved method of contraception
* History or current diagnosis of psychosis, major current depression or bipolar disorder, ADHD, schizophrenia, or any Axis 1 disorder as identified by the MINI
* Serious or unstable disease within the past 6 months (e.g., cancer \[except melanoma\], heart disease, HIV)
* History of epilepsy or a seizure disorder
* History or current diagnosis (last 6-months) of abnormal rhythms and/or tachycardia (\>100 beats/minute); history or current diagnosis of COPD, cardiovascular disease (stroke, angina, coronary heart disease), heart attack in the last 6 months, uncontrolled hypertension (SBP\>150 or DBP\>90)
* Any medical or neurological condition that might interfere with the distribution of the radiotracer as determined by the study MD
* Current or past use (within past 12 months) of any medications containing naltrexone or other MOR antagonists (e.g., Revia, Trexan)
* 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 2 weeks) or planned use of psychotropic medications (anti-psychotics, anti-depressants (tricyclic, SSRI, MAOI), anti-anxiety or panic medications, and stimulants (e.g., Provigil, Ritalin), and opiate-containing medications for chronic pain
* Allergic response to any form of opioids or naloxone
* 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.
* Self-reported history of head trauma or prior seizure, brain (or CNS) tumor
* Self-reported history of claustrophobia (contraindicated for PET)
* Inability to complete the baseline study procedures within four hours and/or correctly, as determined by the principal investigator.