OPRM1 A118G SNP, Alcohol Response, and Striatal Dopamine
Condition: Alcoholism
MeSH terms: Alcoholism
Study type: Observational

Summary: 
      This study will examine the relationship between variations in a gene called OPRM1 and the
      response to alcohol. The OPRM1 (Mu-opioid Receptor-1) gene helps regulate brain pathways
      involved in experiencing pleasure. Brain pathways use a chemical called dopamine. Different
      forms of the OPRM1 gene may lead to differences in how dopamine is released and subsequently
      to differences in a person's response to alcohol.

      Healthy non-smokers between 21 and 45 years of age may be eligible for this study. Candidates
      are screened with a medical and psychiatric history and physical examination, blood and urine
      tests, and breathalyzer (breath alcohol test). A blood test is also done to determine the
      variant of OPRM1 gene.

      Participants undergo the following procedures in three study sessions:

      Session 1

      " Breathalyzer test, urine test for illicit drugs and pregnancy test for women who can become
      pregnant.

      " Insertion of catheters (plastic tubes) into a vein in one arm for infusing alcohol and into
      the other arm for drawing blood samples.

      " Completion of questionnaires on how intoxicated the subject feels.

      " Blood draw for research studies.

      " Eye movement test (a visor with a digital camera tracks the subject's eye movements while
      he or she watches lights on a computer screen).

      " 45-minute alcohol infusion (up to 0,08 grams per deciliter - a level considered in most
      states as driving under the influence of alcohol).

      " Repeat breathalyzer, questionnaires, eye movement test and blood draw every 15 minutes
      during the infusion and again after the infusion is complete.

      " Subjects remain in the clinic until their blood alcohol content falls below 0.02 g/dL,
      determined by a breathalyzer test done every 15 minutes. Subjects can usually return home
      about 3 to 4 hours after the alcohol infusion stops.

      Sessions 2 and 3

      The procedure is the same as for session 1, except subjects receive an infusion of alcohol
      one session and an infusion of saline (salt water) the other. Also, subjects undergo positron
      emission tomography (PET) scanning during the infusions. For this test, the subject lies on a
      bed that slides in and out of a doughnut-shaped scanner. A custom-molded mask is used to
      support the head and prevent it from moving during the scanning. A small amount of
      radioactive substance called C-11 raclopride is injected through one of the catheters to
      trace brain dopamine activity.

      ...
    

Detailed description: 
      Objectives:

      Reinforcing properties of alcohol are in part mediated through endogenous opioids. Mesolimbic
      dopamine (DA) release is a key signal for drug reward, and endogenous opioids are thought to
      exert their effects by modulating the activity of this system. A functional mu-opioid
      receptor (OPRM1) A118G single nucleotide polymorphism (SNP) alters the affinity of the
      mu-opioid receptor for its endogenous ligand, is in some studies associated with increased
      risk for alcohol and heroin addiction, and confers differential pain sensitivity and
      subjective responses to alcohol. This prompts the question whether the differential
      subjective response to alcohol observed as a function of the OPRM1 A118G genotype reflects
      differential activation of the mesolimbic DA release. The objective of this study is to
      examine the role of the A118G OPRM1 polymorphism for responses to a highly standardized
      intravenous alcohol challenge, with regard to psycho-physiological variables measured in the
      laboratory, and for brain dopamine release measured by 11C raclopride PET.

      Study Population:

      We will screen healthy participants from the general population to obtain samples of two
      groups of subjects: 1) persons homozygous for the major 118A allele (118AA genotype); 2)
      persons carrying one or two copies of the variant 118G allele (118AG or 118GG genotype,
      hereafter called 118GX).

      Design and Outcome Measures:

      We will compare the response of these groups to a standardized alcohol challenge using the
      procedure in place for NIAAA protocols 03-AA-0283 Influence of Age and Gender on Alcohol
      Metabolism and Acute Responses and 04-AA-0060 The Effect of Ethanol on Cerebral Blood Flow as
      Measured by Functional Magnetic Resonance Imaging and the Development of Conditioned Response
      to Ethanol Administration . Participants will be given a standardized IV infusion of an
      alcohol solution infused to achieve and maintain a target blood alcohol level of 80 mg%. Pre
      and post infusion measures will be made in two areas: 1) subjective response as measured by
      standardized questionnaires, and 2) measures of physiologic response, to include saccadic eye
      movements and blood chemistries. We hypothesize that 118GX subjects will have significantly
      higher subjective response to alcohol challenge than 118AA subjects. We will then repeat the
      alcohol infusion procedure in all participants twice in the PET scanner, infusing alcohol or
      saline, and assess displacement of 11C raclopride, a positron emitter labeled ligand which
      binds preferentially to D2 receptors. We hypothesize that 118GX subjects will have more 11C
      raclopride displacement after alcohol infusion relative to placebo, indicating greater
      amounts of dopamine release.
    

Time perspective: Prospective
Keywords: PET; C-11 Raclopride; Dopamine; OPRM1; Alcohol; Healthy Volunteer; HV