Alcohol Use
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Investigators led by a researcher from the Ohio State University Wexner Medical Center and College of Medicine report that a one-time administration gene therapy shows potential as a treatment for serious alcohol addiction.

The study, published today in the journal Nature Medicine, used an accepted primate model to show that sustained release of glial-derived neurotrophic factor (hGDNF) in the ventral tegmental area (VTA) of the brain may prevent a return to excessive alcohol use after a period of abstinence. Their findings also showed that it may accomplish this without affecting other motivated behaviors.

“This gene-therapy approach targets changes in dopamine function in the brain’s mesolimbic reward pathway that are caused by chronic alcohol use,” said co-principal investigator Krystof Bankiewicz, MD, PhD, professor of neurological surgery and director of the Brain Health and Performance Center at Ohio State. “Our findings suggest that this treatment can prevent relapse without requiring long-term treatment adherence by patients.”

Excessive use of alcohol has been shown to alter nerve tracks in the brain that are involved in the release of dopamine—often called the “feel good” neurotransmitter. These neurons comprise the mesolimbic pathway, which plays a major role in substance addiction.

These changes become more pronounced as alcohol use disorder (AUD) develops, and include reduced levels of dopamine release, reduced dopamine sensor sensitivity, and increased dopamine uptake. The result is people with AUD have lower levels of dopamine in the pathway.

People with AUD commonly experience repeated cycles of abstinence followed by relapse, even when using one of the few FDA-approved drug therapies, Bankiewicz said.

“At this time, there are no therapies that target circuits in the brain that are altered by sustained, heavy alcohol use,” said co-principal investigator and co-corresponding author Kathleen Grant, PhD, chief and professor of behavioral neuroscience at the Oregon National Primate Research Center, which contributed to this research project.

To conduct the study, the investigators used a rhesus macaque model of AUD. In total, eight rhesus macaques were used in the study which sought to determine whether delivering a viral vector into the brain to induce continuous expression of GDNF could be both practical and effective to diminish alcohol use and also to prevent post-abstinence resumption of drinking.

The vector used for this study was an adeno-associated virus vector that carried a gene for human glial-derived neurotrophic factor (AAV2-hGDNF).

The eight macaques were first habituated to the consumption of 4% alcohol. Four of the animal models were infused with the hGDNF vector directly into the VTA, located in the floor of the midbrain. Neurons in the VTA connect with the mesolimbic reward pathway. The other four macaques were study controls and infused with sterile saline using the same surgical procedure.

The research found that infusion of AAV2-hGDNF significantly blunted alcohol intake across multiple 4-week abstinence and 4-week alcohol-reintroduction cycles. The GDNF-treated animals also showed undetectable blood ethanol levels through the end of the study, while the control group had consistently elevated monthly and weekly alcohol intake and blood ethanol levels across cycles, both as a group and individually.

“Overall, our findings indicate that GDNF gene therapy could diminish reintroduction-associated alcohol intake in our primate model,” Bankiewicz concluded. “We believe this approach shows merit for further study as a promising therapy for AUD and possibly other substance-abuse disorders.”

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