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.
Name: Oral methylphenidate and Oral haloperidolType: Drug
There is one SNP
The impact of rs16969968 genotype on the BOLD fMRI signal and functional connectivity (FC) within and between the three networks of interests (SN, ECN, DMN) at rest and during task performance.. null.
While we will target the A/A homozygotes and G/G homozygotes at the rs16969968 locus, we will also allow A/G heterozygotes to become enrolled in the study.
The enrollment will be open to all racial and ethnic groups, including Caucasians, African Americans, and Asians, as well as Hispanic and non-Hispanics, and we will make an effort to include all racial and ethnic groups as long as all participants meet the rs16969968 genotype criteria.
Justification: The allele frequencies at the rs16969968 locus vary greatly between racial and ethnic groups, making it extremely difficult to ensure a balance of ethnicities across the genotype groups.
In particular, the minor A allele of rs16969968 (the Risk allele in the current study), associated with increased risk of heavy smoking and nicotine dependence, has a frequency of 0.42 in Caucasians, but is very rare in Asians (0.03) and African Americans (0.07) (Saccone et al., 2010b).
Importantly, because the association between the rs16969968 locus and nicotine addiction severity has been demonstrated in all three ethnic groups in a recent meta-analysis (Chen et al., 2012), we argue that the racial and ethnic groups not enrolled in the current study will still benefit from basic, mechanistic knowledge gained from this study if translated to clinical treatment and prevention of nicotine abuse and dependence in the future.
Additionally, we will examine ancestry information markers to verify and extend the self-reported ethnic background and to test for possible modulatory effects of specific genetic-ancestry groups with respect to the rs16969968 effects in our data.
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).
We have previously shown that resting-state connectivity of the SN is decreased in smokers and non-smokers with the rs16969968 risk allele.
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.
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 ).
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.