"Impulsivity is a risk factor for addiction to many substances, and it has been suggested that people with lower dopamine levels in the frontal cortex tend to be more impulsive," said lead author Andrew Kayser, PhD, an investigator at Gallo and an assistant professor of neurology at UCSF. "We wanted to see if we could decrease impulsivity by raising dopamine, and it seems as if we can."
The study was published on July 4 in the Journal of Neuroscience.
In a double-blinded, placebo-controlled study, 23 adult research participants were given either tolcapone, a medication approved by the Food and Drug Administration (FDA) that inhibits a dopamine-degrading enzyme, or a placebo. The researchers then gave the participants a task that measured impulsivity, asking them to make a hypothetical choice between receiving a smaller amount of money immediately ("smaller sooner") or a larger amount at a later time ("larger later"). Each participant was tested twice, once with tolcapone and once with placebo.
Participants – especially those who were more impulsive at baseline – were more likely to choose the less impulsive "larger later" option after taking tolcapone than they were after taking the placebo.
Magnetic resonance imaging conducted while the participants were taking the test confirmed that regions of the frontal cortex associated with decision-making were more active in the presence of tolcapone than in the presence of placebo.
"To our knowledge, this is the first study to use tolcapone to look for an effect on impulsivity," said Kayser.
The study was not designed to investigate the reasons that reduced dopamine is linked with impulsivity. However, explained Kayser, scientists believe that impulsivity is associated with an imbalance in dopamine between the frontal cortex, which governs executive functions such as cognitive control and self-regulation, and the striatum, which is thought to be involved in the planning and modification of more habitual behaviors.
"Most, if not all, drugs of abuse, such as cocaine and amphetamine, directly or indirectly involve the dopamine system," said Kayser. "They tend to increase dopamine in the striatum, which in turn may reward impulsive behavior. In a very simplistic fashion, the striatum is saying 'go,' and the frontal cortex is saying 'stop.' If you take cocaine, you're increasing the 'go' signal, and the 'stop' signal is not adequate to counteract it."
Kayser and his research team plan a follow-up study of the effects of tolcapone on drinking behavior. "Once we determine whether drinkers can safely tolerate this medication, we will see if it has any effect on how much they drink while they're taking it," said Kayser.
Tolcapone is approved as a medication for Parkinson's disease, in which a chronic deficit of dopamine inhibits movement.
Co-authors of the paper are Daicia C. Allen, BS, Ana Navarro-Cebrian, PhD, Jennifer M. Mitchell, PhD and senior author Howard L. Fields, MD, PhD, of the Gallo Center and UCSF.
The study was supported by funds from the Wheeler Center for the Neurobiology of Addiction, the U.S. Army Telemedicine and Advanced Technology Research Center, the Alcoholic Beverage Medical Research Foundation/The Foundation for Alcohol Research and the State of California.
The UCSF-affiliated Ernest Gallo Clinic and Research Center is one of the world's preeminent academic centers for the study of the biological basis of alcohol and substance use disorders. Gallo Center discoveries of potential molecular targets for the development of therapeutic medications are extended through preclinical and proof-of-concept clinical studies.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
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