OPRM1 A118G SNP, Alcohol Response, and Striatal DopamineStudy Type: Observational Study Design: Natural History, Longitudinal, Defined Population, Prospective Study
Official Title: OPRM1 A118G SNP, Alcohol Response, and Striatal Dopamine
Further study details as provided by National Institutes of Health Clinical Center (CC):
Expected Total Enrollment: 60
Study start: November 2006
BACKGROUND:
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.
AIMS:
To examine the role of the A118G OPRM1 polymorphism for responses to a highly standardized intravenous alcohol challenge, with regard to psychophysiological variables measured in the laboratory, and for brain dopamine release measured by C-11 Raclopride PET.
METHODS:
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).
We will compare the response of these groups to a standardized alcohol challenge using the procedure in place for NIAAA protocols 03-AA-0283 and 04-AA-0060. 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 C-11 raclopride displacement after alcohol infusion relative to placebo, indicating greater amounts of dopamine release.
Official Title: OPRM1 A118G SNP, Alcohol Response, and Striatal Dopamine
Further study details as provided by National Institutes of Health Clinical Center (CC):
Expected Total Enrollment: 60
Study start: November 2006
BACKGROUND:
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.
AIMS:
To examine the role of the A118G OPRM1 polymorphism for responses to a highly standardized intravenous alcohol challenge, with regard to psychophysiological variables measured in the laboratory, and for brain dopamine release measured by C-11 Raclopride PET.
METHODS:
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).
We will compare the response of these groups to a standardized alcohol challenge using the procedure in place for NIAAA protocols 03-AA-0283 and 04-AA-0060. 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 C-11 raclopride displacement after alcohol infusion relative to placebo, indicating greater amounts of dopamine release.
