A type of gene therapy being trialed for Parkinson’s disease could reset dopamine pathways in the brain and curb the desire to drink in patients with severe alcohol use disorder, new research suggests.
Gene therapy could reset the dopamine pathways of addiction
Rhesus monkeys addicted to alcohol dramatically reduced their consumption after being treated with a gene for the glial-derived neurotrophic factor (GDNF), researchers at Oregon Health and Science University (OHSU) found, in a study published in Nature Medicine earlier this month.[1]
The protein glial-derived neurotrophic factor (GDNF) enhances the function of brain cells that synthesize dopamine. It’s being trialed as a treatment for Parkinson’s disease and for the rare genetic disorder aromatic L-amino acid decarboxylase deficiency (AADCD).[2]
A deficiency of dopamine can cause the movement problems of Parkinson’s and AADCD and is also thought to underly addiction, including alcoholism.
Like other addictive substances, alcohol triggers the release of the feel-good neurotransmitter. Chronic exposure to alcohol down-regulates dopamine receptors, leading to dysphoria (sadness) in the absence of drinking and perpetuating addiction. This dysphoria in the absence of alcohol is one of the primary causes of relapse in alcoholics and one of the main obstacles to recovery.
“A big problem in treating alcohol use disorder is the return to drinking after abstinence is achieved. So that's really what we wanted to address,” said Professor Kathleen Grant from OHSU’s National Primate Research Centre.[3]
She and her colleagues wondered if GDNF could reset the dopamine reward pathways hijacked by addiction, helping patients achieve and maintain abstinence.
“We wanted to see if we could normalize the dopamine in these motivational areas – if, indeed, motivation to overdrink or drink heavily would be mitigated,” said Grant.[4]
Monkeys treated with the gene sustainably reduced their alcohol intake by up to 90%
To test the use of GDNF, researchers used rhesus macaques. These primates have previously been shown to voluntarily drink intoxicating amounts of alcohol (eight to ten standard units) for months to years and have been used to model alcohol use disorder (AUD). Like among humans, some macaques appear more predisposed to alcohol addiction.
In this study, macaques were offered 5% alcohol—around the same strength as beer— alongside their food and water, with some always choosing alcohol.
Grant and her colleagues used a harmless virus to insert the gene coding for the GDNF protein into the brains of four heavy-drinking macaque monkeys. An MRI guided them to inject the virus into the ventral tegmental area (VTA), a key cog in the brain’s reward circuitry.
“We targeted the cell bodies that produce dopamine with this gene to increase dopamine synthesis, thereby replenishing or restoring what chronic drinking has taken away,” Grant said.[2]
The trial found that macaques treated with the gene for GDNF began producing more dopamine and reduced their alcohol intake by up to 90%, to less than two standard drinks per day. These changes were permanent, with the reduction in alcohol consumption sustained over one year, despite continued access.
The control group of macaques, treated with an inactive form of the gene, continued drinking.
Gene could be a one-time treatment for severe alcohol use disorder
Next are more animal trials before the gene therapy can be tested in humans. However, the initial positive results in monkeys suggest it could be a potent treatment for alcoholism and potentially other types of addiction.
However, because the treatment is irreversible and involves brain surgery, it would only be used in patients with severe alcohol use disorder.
“It would be most appropriate for individuals for which all other forms of therapy have not worked,” Grant said. “You don’t really want to go to an invasive and irreversible therapy unless someone’s life is at stake.”[2]
She also cautioned against generalizing the effectiveness of the treatment for other addictions. “It would have to be carefully studied for any kind of stimulant addiction because that is so involved directly in the dopamine pathways,” she said.[3]