Stem Cell Study of Genetics and Drug Addiction

Development of Induced Pluripotent Stem Cells Carrying Monoamine Transporter Polymorphisms

Background:

- Researchers are interested in studying the roles that genes play in drug and alcohol addiction. Genes seem to account for about half of the differences between people who become addicted to drugs and people who do not. This study will collect blood and skin cell samples. These cells will be used to develop stem cells that are useful for studying how genes are related to drug use and dependence.

Objectives:

- To study genetic and cellular differences between people who are addicted to drugs and those who are not.

Eligibility:

• Individuals between 21 and 65 years of age who do not use drugs.
• Individuals between 21 and 65 years of age who are in treatment with buprenorphine or methadone.

Design:

• Participants will be screened with a brief physical exam and medical history.
• Participants will also answer questions about physical and mental health, quality of life, and history of drug and alcohol use. A urine sample and cheek swab sample will be collected.
• Participants whose genetic samples match the study requirements will be asked to come back to provide a skin biopsy sample and a second urine sample.

Study Overview

• Status: Completed
• Conditions: Induced Pluripotent Stem Cells

Detailed Description

Background - The molecular- and cellular-based mechanisms that contribute to the initiation and development of addiction remain to be elucidated. Estimates have suggested that 40-60 percent of the vulnerability to addiction may be attributable to genetic aberrations. Multiple chromosomal regions have been linked to addiction including those containing the dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) genes. Current efforts to understand how polymorphisms in these monoamine transporters contribute to the molecular mechanisms of addiction are severely hindered by the inability to directly interrogate neural cell types from the patients. There is great potential for patient-specific iPS cell technology to profoundly impact our understanding of human development and disease by providing genetically distinct, functional sources of human cells.

Objective - The objective of the research is to develop a cell-based system whereby neural cells from afflicted individuals can be functionally assayed to interrogate the molecular mechanisms underlying addiction.

Study population Controls (non-drug users) and opioid dependent adults receiving opioid agonist therapy aged 21- 65 will be enrolled.

Design Participants demographic characteristics, psychosocial evaluation, and psychiatric, medical, and drug use histories will be characterized. DNA will be collected via cheek swabs of up to 30 potential participants for determination of dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) gene polymorphisms. Participants (N=16) with suitable polymorphisms will be asked to under go skin biopsies; 2 individuals for each of two genotypes for each gene (DAT or VMAT), i.e., 8 samples from addicts and 8 samples for control subjects. Collaborators at Case Western Reserve University will use the skin cells to derive and characterize patient-specific, induced pluripotent stem (iPS) cells that carry monoamine transporter polymorphisms for the hDAT1 and hVMAT2 genes. They will differentiate patient-specific iPS cells line into dopaminergic neurons and carry out a detailed and functional characterization of these cells to identify their molecular characteristics.

Outcome measures - Biological specimens from the addiction patients and controls will be used to derive and characterize patient-specific, induced pluripotent stem (iPS) cells that carry monoamine transporter polymorphisms. Patient-specific iPS cells lines will be differentiated into dopaminergic neurons. In follow up studies, we will characterize, compare, and functionally assay these patient-specific, iPS cell-derived dopaminergic neurons from control and addiction patients that carry polymorphisms for hDAT1 and hVMAT2 gene to investigate any possible association with dopamine neurotransmission variations and vulnerability to addiction.

• Study Type: Observational
• Enrollment (Actual): 49

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • National Institute on Drug Abuse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

  1. 21 to 65 years old

     Opioid dependent participant group only:

  2. enrollment in a substance abuse treatment protocol in Archway.

     Non-drug users

  3. no lifetime history of drug dependence as indicated by the screening ASI and Substance Abuse/Dependence Evaluation counselor interview.

EXCLUSION CRITERIA:

1. Relevant neurological disorders (including, but not limited to, Parkinson s disease and Huntington s disease).
2. contraindications to skin biopsy including, but not limited to, bleeding disorders, skin disorders, and immune disorders, that the MAI determines may alter the risk of the biopsy.
3. cognitive impairment severe enough to preclude informed consent or valid responses on questionnaires.
4. controls will also be excluded if they test positive for drugs or alcohol during screening or study visits.
5. unwillingness to allow samples to be kept for future research.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Derive and characterize patient-specific, induced pluripotent stem (iPS) cells that carry monoamine transporter polymorphisms and differentiate them into dopaminergic neurons.

Collaborators and Investigators

• Sponsor: National Institute on Drug Abuse (NIDA)

Publications and helpful links

General Publications

• Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychol Rev. 1987 Oct;94(4):469-92. No abstract available.
• Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci. 2001 Oct;2(10):695-703. doi: 10.1038/35094560.
• Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2001 Feb;2(2):119-28. doi: 10.1038/35053570. Erratum In: Nat Rev Neurosci 2001 Mar;2(3):215.

Study record dates

Study Major Dates

• Study Start: February 7, 2012
• Study Completion: July 30, 2014

Study Registration Dates

• First Submitted: February 15, 2012
• First Submitted That Met QC Criteria: February 15, 2012
• First Posted (Estimate): February 16, 2012

Study Record Updates

• Last Update Posted (Actual): December 17, 2019
• Last Update Submitted That Met QC Criteria: December 14, 2019
• Last Verified: July 30, 2014

More Information

Terms related to this study

• Keywords: Addiction; Dopamine Transporter; Addiction-Associated Human Gene Variants; Induced Pluripotent Stem Cell (iPS) Cell Lines
• Other Study ID Numbers: 999912476; 12-DA-N476