Alcohol use disorder affects tens of millions of people worldwide, resulting in huge economic losses and serious public health impacts. Chronic conditions are defined by a loss of control over drinking habits and severe negative emotional states when the drug is no longer taken.
Several drugs have been approved to treat this disorder, but they are only effective for some patients. In a recent study, researchers found that genetic markers associated with specific brain receptors predicted the severity of alcoholism in rodents, and that administration of the antiparasitic drug ivermectin reduced withdrawal-induced drinking. The study was published in the journal neuropharmacology.
Due to the wide biological and genetic diversity of patients, current drug treatments for alcohol use disorder often fail to provide lasting symptom relief. Chemical interventions that are successful in controlling drinking in one person may cause side effects or have no measurable effect in another. To improve psychiatric care, medical practices must adopt a precision medicine model that takes these deeply ingrained individual differences into account.
A collaborative team of scientists led by Paola Campo, Marcida Carpi, and Giordano de Guglielmo at the University of California, San Diego sought to understand how certain genetic mutations influence addictive behavior. They focused on a gene called *P2rx4*. This gene contains instructions for building P2X4 receptors, specialized protein channels on the surface of brain cells.
These receptors are highly concentrated in areas of the brain associated with stress and reward processing. Under normal conditions, they help regulate the flow of electrical signals between neurons. When a person consumes alcohol, the substance acts as an inhibitor, temporarily reducing the activity of these receptor channels.
In response to chronic alcohol exposure, the brain attempts to compensate by producing more of these receptors. Previous studies have linked this receptor cluster to drinking behavior in a variety of animal models, but the precise relationship in naturally diverse genetic populations remains largely unknown. The researchers hypothesized that baseline variations in this gene might determine which people are more likely to increase their drinking over time.
To test this idea, the researchers utilized a cross-species stock of rats. Unlike traditional laboratory strains that are bred to be genetically identical, heterogeneous stock rats are bred from eight different source populations. This breeding strategy creates a large gene pool, producing rodents with unique physical characteristics and behavioral tendencies that more closely reflect human diversity.
Rather than directly tracking physical proteins in the brains of living animals, the researchers applied advanced computational models to existing genetic databases. They looked for specific mutations in DNA sequences located near their target genes. By analyzing these small genetic spelling differences across 131 different rats, the tool predicted how reliably a gene would be expressed in each animal’s brain tissue.
Based on these statistical calculations, the research team divided the rodents into groups with high predicted expression levels and groups with low predicted expression levels. Animals were first trained in a dedicated conditioning chamber and learned to press a mechanical lever to receive small droplets of alcohol.
After establishing a stable baseline of spontaneous intake, the researchers exposed the rodents to daily cycles of alcohol vapor within the housing unit. This chronic intermittent vapor model reproduces physical dependence in humans by maintaining highly elevated blood alcohol concentrations over long periods of time, followed by a period of forced abstinence.
The researchers found that rodents assigned to the high predicted expression group increased their alcohol intake much more strongly during withdrawal than other animals. Both groups consumed more alcohol after becoming addicted, but the genetically susceptible rats had a much heavier burden of compulsive drinking.
Following this genetic analysis, the researchers considered possible pharmaceutical interventions. They tested ivermectin, a common drug commonly prescribed in veterinary and human medicine to treat parasitic infections. Previous cellular studies demonstrated that ivermectin acts on the P2X4 receptor and increases its activity, essentially counteracting the biological dampening effects caused by alcohol.
A separate cohort of 32 dependent, genetically diverse rodents received various doses of ivermectin by injection 4 hours before behavioral testing. The drug reduced alcohol consumption in a dose-dependent manner. Animals given the highest dose had significantly reduced lever pressing for alcohol during the acute withdrawal period.
The researchers also needed to make sure that the drug was directly altering the brain’s motivational system, rather than simply slowing down the animals’ bodies. They monitored the rodents’ water intake throughout the pharmacological study. It was found that the drug did not alter the animals’ desire to drink water and specifically reduced alcohol-seeking behavior without causing systemic movement disorders.
However, researchers observed differences between men and women. Female rodents consumed more alcohol on average and required higher doses of ivermectin to show reduced drinking compared to male subjects. Because of the extensive genetic variation among subjects, the drug did not work universally across the population.
The researchers stratified the animals based on specific behavioral responses to the drug, dividing them into non-responders, mild responders, and high responders. To find out exactly why the drug only works in certain subjects, scientists prepared incredibly thin slices of rodent brains and kept the tissue alive in a bath of oxygenated liquid.
They focused specifically on the central amygdala, a dense cluster of neurons that acts as a major hub for processing fear, stress, and negative emotional states. They used microscopic glass electrodes to record weak electrical currents flowing across the membranes of individual brain cells within this region.
This advanced technology makes it possible to observe the activity of gamma-aminobutyric acid, commonly known as GABA, in real time. This chemical acts as a major inhibitory messenger in the mammalian nervous system, acting like a biological brake pedal to slow down uncontrolled electrical firing. During the acute phase of alcohol withdrawal, this braking system becomes severely dysregulated.
In highly responsive animals, soaking brain slices in ivermectin produced a sustained increase in the frequency of calming GABA signals. This suggests that the drug may have successfully engaged the target receptor and promoted the release of inhibitory chemicals, which reduced the animal’s internal urge to drink.
The drug had very different results in animals that did not respond. Although the precise timing of the current changed slightly, we were unable to increase the overall frequency of the inhibitory signal. The researchers suspect that in these animals, the drug interacted with other collateral receptors on the cell surface rather than properly engaging the primary targeting mechanism.
There are major hurdles in moving drugs from rodent experiments to human clinics. Ivermectin often has a hard time crossing the blood-brain barrier, which acts as a protective shield for cells around the human central nervous system. Achieving the required drug concentrations in the human brain can be difficult with standard oral tablet administration alone.
Future studies will address delivery issues of these chemicals. Scientists may explore combination therapies that combine ivermectin with complementary chemicals that temporarily bypass the brain’s defense pumps and allow more of the drug to reach the central amygdala. Other studies will attempt to map precisely which types of brain cells express these target receptors most in order to narrow the mechanistic focus.
Ultimately, this study highlights the need to match the right pharmacological treatment to the right genetic profile. Future clinical trials evaluating this cellular pathway may require pre-screening human participants for specific genetic markers. By identifying who is biologically more likely to respond, medical professionals will eventually be able to provide precisely tailored treatment for severe alcohol dependence.
The study, “Ivermectin reduces withdrawal-induced alcohol intake in rats: association with CeA GABAergic enhancement and P2rx4 genetic liability,” was authored by Paola Campo, Ran Qiao, Michelle R. Doyle, Daniel Munro, Benjamin J. Johnson, Abraham A. Palmer, Marsida Kallupi, and Giordano de Guglielmo.
