Scitech | Liquored up lab rats

New gene therapy could cure rodents of their alcoholism

Researchers at the University of Maryland may have found a way to cure alcoholism in binge drinking rats. Rather than applying current techniques of psychosocial and pharmacotherapeutic intervention, the team, led by Harry L. June, professor of Psychiatry and Pharmacology at the university’s School of Medicine, used gene therapy to treat the alcoholic rodents.

The rats were first given a taste for booze with an invitation to an open bar. They were trained to self-administer doses of an ethanol-saccharin cocktail by pressing a lever – four lever presses for a 0.1 mL shooter. Over a two-week period, the rats were then weaned off the saccharin and slowly introduced to a 10 per cent ethanol-only solution. With an understanding of the lever mechanism and a maturing palette for spirits, the rats were ready to party. The University of Maryland researchers exposed their subjects to thirty-minute binge drinking sessions for three days. While binging, the rats were given a choice between the ethanol solution and water, and after each session tested for blood alcohol content. Rats with blood alcohol content greater than 0.08 per cent (the cutoff for excessive drinking as defined by the National Institute on Alcohol Abuse) were considered to have a preference for alcohol, and were then selected to receive gene therapy.

The team found that the desire to binge drink was linked to the reward circuitry in mammalian brains. In rats, the protein αalpha-1 subunit – a receptor located en masse in the brain’s ventral pallidum – is the culprit. In humans, preliminary testing indicates that the αalpha-2 subunit is linked with impulsivity, anxiety, and drug abuse.

Using the Herpes Simplex virus as a vector – a vehicle for the transfer of genetic material to a target cell – June and his team introduced small interfering RNA chains into the ventral pallidum, inhibiting αalpha-1 subunits, and virtually eliminating the rats’ desire for excessive alcohol consumption. The rodents showed no desire to drink for six days after the surgery, but began drinking increasingly soon after, reaching pre-surgery levels on day 13. The duration of the effects represents one of the most important flaws in current gene therapy, and is a barrier between clinical trial and human application. Due to rapid cell division, lasting effects of gene therapy are difficult to sustain. Fortunately, the vector used in the treatment isn’t toxic, inhibiting only its specific target cells: it caused no loss of body weight and did not alter general activity levels.

Before gene therapy can be used to help cure alcoholism in humans, conclusive evidence must link the αalpha-2 subunit to alcohol dependence. Researchers will need to exhaustively explore the molecular pathways of the subunit proteins and determine if procedures are safe. June hopes to use the information generated in the study to develop drugs that could use the subunit receptors to their full advantage, bypassing the need for vectors. If testing is successful, gene therapy as a cure for alcoholism may lie in the near future; thanks, in part, to a few sober rodents.


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