Compulsive drinking in rats linked to hyperactive NMDARs in the prefrontal cortex

Tina Pentland: News Editor

A team of scientists at the Ernest Gallo Clinic and Research Center at UC San Francisco have identified a molecule that can—quite literally—turn off or on the compulsion to drink and the means to control this type of compulsive behaviour in rats. Although compulsive drinkers may be fully aware of the negative consequences of excessive and uncontrolled drinking they are, by definition, unable to regulate their compulsion—in other words, they ignore the warning signals in the brain that normally alert a person (or animal) to danger. This type of addictive behaviour is described as “aversion resistant”, meaning that addicts will continue the behaviour not only in the face of known harmful effects but even in the face of other deterrents, such as an unpleasant taste.

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The study, “Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake,” published online in the journal Nature Neuroscience, investigated the hypothesis that abnormal activity in the prefrontal cortex is caused by a particular molecule that produces aversion resistant (or compulsive) behaviour. The prefrontal cortex is the area of the brain associated with risk-assessment and reward, which is responsible for decision-making and critical self-awareness—hence its role in controlling compulsive behaviour. In the study described here, the research team examined brain activity in the prefrontal cortex of rats when offered regular alcohol, or alcohol laced with quinine. They found that the drinking or “aversion resistant” rats (i.e., those who drank the quinine-laced alcohol and could thus be called compulsive drinkers), showed a notable increase in the NMDA receptor (NMDAR), which caused unusual excitation in this area of the brain. The researchers identified the molecule responsible for this as a glutamate which produces a “hyperglutamergic state” that subsequently promotes aversion-resistant behaviour. When the rats were injected with an NMDAR blocker, their consumption of the quinine-laced alcohol dropped significantly. Then, using a technique called “optogenetics”, the researchers inserted halorhodopsin, a light-sensitive protein which worked to directly inhibit the neural connections to the nucleus accumbens and hence prevent the unwanted flow of information that encourages the abnormal behaviour.

The role of the medial prefrontal cortex (mPFC) in controlling addictive behaviour is well-recognized; however, little is known about the neural or molecular underpinnings of this behaviour. This study is important, therefore, not only for opening up this area of research but also for finding further means of intervention to treat or control compulsive behaviours. As the authors note, compulsive drinking is a major clinical problem but it is very hard to treat. It can cause untold misery to individuals and is also a severe burden to society—in the United States alone alcoholism is estimated to cost $224 billion per year, mostly from lost productivity and crime, and leads to 100,000 preventable deaths per year. Thus, it is hoped that this study will be followed up with further clinical trials in humans, which will then lead to the development of targeted treatments for compulsive drinking and other substance use disorders, and improve treatment outcomes