PET imaging of dopamine release in the brain has identified a genetic variant of dopamine responses to alcohol, a mechanism likely to modulate alcohol reward, according to a study published May 18 in Molecular Psychiatry.
Humans vary greatly in their alcohol responses and this variation is related to genetic susceptibility for alcoholism, which contributes to more than half of alcoholism risk, the authors wrote.
The study, conducted by Vijay A. Ramchandani, PhD, an investigator and acting chief of section on human psychopharmacology at the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health in Bethesda, Md., and colleagues, explored whether a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol.
Using human PET imaging and [11C]-raclopride displacement, Ramchandani and colleagues compared dopamine release in two groups of people that had been given a dose of alcohol. The groups consisted of those who carried a copy of the gene for the 118G mu-opioid receptor variant, and those who carried only genes for the more common 118A variant.
The researchers found that only people with the 118G variant had a dopamine response to alcohol — no such response happened in subjects with the 118A receptor variant.
To directly establish the causal role of OPRM1 A118G variation, Ramchandani and colleagues generated two humanized mouse lines, carrying the respective human sequence variant and then directly measured the animals’ dopamine response to a dose of alcohol.
Brain microdialysis showed that mice with the 118G variant had a fourfold higher peak dopamine response to the alcohol challenge compared to mice with the 118A variant, according to Ramchandani and colleagues.
"Taken together, our data strongly support a causal role of the 118G variant of the mu-opioid receptor to confer a more vigorous dopamine response to alcohol in the ventral striatum," said Ramchandani.
"The findings add further support to the notion that individuals who possess this receptor variant may experience enhanced pleasurable effects from alcohol that could increase their risk for developing alcohol abuse and dependence. It may also explain why these individuals, once addicted, benefit more from treatment with blockers of endogenous opioids," the authors wrote.