Impulsivity is defined as behavior performed with little or insufficient forethought. Another more technical description is disinhibition of reward-driven behavior that is not appropriate for the current demands. Impulsivity has strong correlations with substance abuse, including alcohol addiction. People with impulsive behavior may be more at risk for addiction, and degeneration due to chronic alcohol abuse can increase impulsivity, progressing severity of the disorder. Understanding the connection between impulsivity and addiction may lead to better treatments for substance abuse. However, their relationship is relatively unknown. In this post, we will follow the work of two scientists who demonstrate the persistence and curiosity required for biomedical discoveries.
Scientists can recreate alcohol addiction using transgenic mice. These mice lack a particular transporter known to function in alcohol consumption called ENT1, or equilibrative nucleoside transporter 1. After drinking alcohol, this transporter is inhibited. Mice without this transporter protein are less affected by alcohol and tend to consume more than normal mice, mimicking alcohol addiction in humans.
Normally, ENT1 transports adenosine, a neuromodulator that has an inhibitory effect on the central nervous system. When ENT1 can’t transport adenosine, it is unable to regulate excitation in the brain and tell it to “slow down.” In other words, alcohol keeps the foot off the brakes, possibly promoting impulsivity.
Alfredo Oliveros is a Mayo Graduate School PhD candidate in the lab of Dr. Doo-Sup Choi at the Mayo Clinic College of Medicine. He is using these transgenic ENT1 negative mice to discover exactly how alcohol addiction alters adenosine levels in order to cause impulsive behavior.
So, how do you measure impulsivity? A famous example of impulsivity in humans is the marshmallow test. In this test, children are told they could have one marshmallow now, or wait and receive more marshmallows later. The more impulsive kids are unable to wait for more marshmallows, and instead eat the one and receive instant gratification.
Oliveros translated the marshmallow test for mice to test their impulsivity. Mice were trained to get food from a receptacle only when a special sound-cue is played. However, if they were impulsive (i.e. were unable to wait for the next sound-cue) and checked the receptacle, their next opportunity for the reward was delayed. Impulsive mice would check the food receptacle frequently, while less impulsive mice were able to wait. He also used a test, which differed in that the reward was only provided when a certain pattern of lights was illuminated, adding a cognitive aspect to the test.
Oliveros found that the alcohol preferring ENT1-negative mice were more impulsive than normal mice and checked the food receptacle frequently. Since ENT1 transports adenosine, he then studied the involvement of adenosine as the next step between alcoholism and impulsivity. To promote impulsive behavior, adenosine binds to a particular receptor on neurons involved in inhibitory behavioral control. Oliveros used a drug to antagonize that receptor, blocking any downstream effects. Once again, he saw that impulsivity was increased, suggesting that adenosine is the brake that controls impulsivity.
If ENT1 regulated adenosine levels to promote addiction and impulsivity, what did adenosine regulate? You can see that scientists are never content with one answer. They are always asking, “why,” tunneling further and further toward the truth. Oliveros and Choi knew that the adenosine receptor activated a protein called ERK. Was ERK also responsible for enhanced impulsiveness in alcoholism? To test this question, the scientists used a drug to inactivate ERK and examined the mice for impulsive behavior. Sure enough, mice with inactive ERK demonstrated more impulsivity.
ERK plays many roles in the brain, one of which is cell proliferation. Normally, brain cells do not divide. However, it has been discovered that neurogenesis, or the creation of new neurons in the brain, does occur. The function of neurogenesis is still unclear, though current studies implicate neurogenesis with learning and memory. Could modulation of impulsivity be a novel function of neurogenesis via ERK?
Interestingly, neurogenesis was reduced in the ENT1 negative mice that displayed alcoholic and impulsive behavior. It appears that alcohol addiction promotes impulsivity by inhibition of adenosine, which inactivates ERK. ERK caused a reduction in neurogenesis, suggesting a new role for neurogenesis in alcohol addiction and impulsivity. How do altered levels of neurogenesis cause these behaviors? The questions continue, and Oliveros and Choi will continue to follow the trail.
By mapping out the connections between addiction, impulsivity, and neurogenesis, Oliveros and Choi provide potential targets for therapeutics to treat alcohol addiction. Scientists such as these who persist, continuing to ask “why,” are the key to future drug discoveries and improved lives.
Choi, D.S., et al. (2004) The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nature Neuroscience. 7: 855.
Nam, H.W., et al. (2013) Adenosine Transporter ENT1 Regulates the Acquisition of Goal-Directed Behavior and Ethanol Drinking Through A2A Receptor in the Dorsomedial Striatum. Journal of Neuroscience. 33: 4329.
Verdejo-García, A., et al. (2008) Impulsivity as a vulnerability marker for substance-use disorders: Review of findings from high-risk research, problem gamblers and genetic association studies. Neuroscience and Biobehavioral Reviews. 32: 777.