Brain Networks and Addiction Susceptibility
Condition: Nicotine Dependence
MeSH terms: Tobacco Use Disorder
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - The risk for becoming addicted to drugs varies from person to person, even among those
      using similar drugs in a similar way. Researchers do not fully understand why some people
      become addicted to drugs and others do not. Studies suggest that under certain life
      circumstances, some genes may increase the risk for addiction. This study will use genetic
      information, computer tasks, magnetic resonance imaging (MRI), and other tests to see what
      brain networks may be related to drug addiction.

      Objectives:

      - To better understand brain networks that may be related to susceptibility to drug
      addiction.

      Eligibility:

      - Healthy non-smoking volunteers between 18 and 55 years of age.

      Design:

        -  This study will have one screening visit and four all-day study visits. For male
           participants, the visits will be about 7 days apart over 5 to 7 weeks. Female
           participants will have the visits scheduled to coordinate with their menstrual cycle.

        -  This study involves small doses of three approved drugs: two oral dopamine drugs and a
           nicotine patch. For each scanning session, participants will have three study drugs.
           However, only one pill or patch will be the real drug; the other two will be placebos.
           Some participants may have only placebos during a visit.

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be taken. Other tests will be given to ensure that participants are not
           smoking or using drugs while they are in the study.

        -  During the all-day scanning visits, participants will receive two pills and one patch in
           the morning and they will be trained on simple computer tasks. In the afternoon,
           participants will have MRI scans and we will measure their brain activity while they
           rest and while they perform computer tasks in the scanner. Participants will also answer
           questionnaires during the scanning visits.
    

Detailed description: 
      Objective. Identification of genetic risk factors predisposing to nicotine abuse and
      dependence, and elucidation of their neurobiological mechanisms of action, is critical to
      individualized treatments and prevention of nicotine addiction. Nicotine exerts its effects
      on the brain through nicotinic acetylcholine receptors (nAChRs). The non-synonymous single
      nucleotide polymorphism (SNP) rs16969968 in the CHRNA5 gene encoding the 5 subunit of nAChRs
      has been unequivocally associated with smoking behavior and nicotine dependence in
      genome-wide association studies (GWAS). At the brain level, the salience network (SN) or the
      neural circuitry connecting the anterior insula (AI), dorsal anterior cingulate cortex
      (dACC), the ventral striatum (VS), and extended amygdala has been shown to be crucially
      involved in nicotine addiction. The SN detects salient events and initiates a rapid switch
      between large-scale brain networks, the default-mode network (DMN) and executive control
      network (ECN), in control of behavior. Genetic influences on the SN may therefore explain
      some of the individual differences in susceptibility to addiction. We have previously shown
      that resting-state connectivity of the SN is decreased in smokers and non-smokers with the
      rs16969968 risk allele. But the underlying neurobiological processes are still unknown. Given
      a well-established role of dopamine (DA) in addiction, and the presence of nAChRs on DA
      neurons, one plausible mechanism involves cholinergic modulation of DA transmission.
      Consequently, we will employ an integrative imaging pharmacogenetics approach to test for DA
      mediation of the rs16969968 effects on the SN in healthy non-smoking participants, with the
      goal of elucidating the neurobiological mechanism underlying the association between this SNP
      and susceptibility to nicotine dependence without the confound of chronic smoking.

      Study Population. Sixty pre-screened participants will be classified into two equal groups (n
      = 30 per group) based on their rs16969968 genotype: 1) rs16969968 risk allele homozygotes, or
      A/A genotype ( Risk Group ); and 2) rs16969968 non-risk allele homozygotes, or G/G genotype (
      Non-Risk Group ). Participants will be healthy, right-handed males and females, aged 18-55,
      non-smokers and free of lifetime substance dependence.

      Design. A double-blind, placebo-controlled crossover design will be used. Each participant
      will complete a screening session (under the Screening Protocol 06-DA-N415); an orientation
      session, which will include a nicotine patch tolerance test; and 4 imaging visits, each with
      a different pharmacological pre-treatment prior to scanning: 1) placebo pill + placebo patch;
      2) 20 mg oral methylphenidate + placebo patch; 3) 2 mg oral haloperidol + placebo patch; and
      4) placebo pill + 7 mg nicotine patch.

      Outcome Measures. The study will use neuroimaging (fMRI) to assess the impact of rs16969968
      genotype and drug condition (MPH vs. haloperidol vs. nicotine vs. placebo) on the SN, ECN,
      and DMN function at rest and during task performance. The primary outcome measures will be:
      1) network coherence, as indexed by resting-state and task-related functional connectivity
      (FC); 2) dynamic task-related interactions; and 3) behavioral task performance. We will also
      test for genetic effects on 4) self-report measures of impulsivity and other traits
      associated with addiction susceptibility.
    

Intervention name(s): Oral methylphenidate and Oral haloperidol
Intervention type(s): Drug
Intervention MeSH terms: Haloperidol; Haloperidol decanoate; Methylphenidate
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Primary purpose: Prevention
Keywords: Cognitive Control; fMRI; Genetics; Dopamine