May/June 2001 Article 1 Article 2

Prenatal Ethanol Reduces the Activity of Adult Midbrain Dopamine Neurons Roh-Yu Shen, Ph.D., John H. Hannigan, Ph.D., and Gregory Kapatos, Ph.D. Abstracted from Alcoholism: Clinical and Experimental Research, 23, 1801-1807, 1999. Drs. Shen, Hannigan, and Kapatos conducted this work together at the Wayne State University Fetal Alcohol Center in Detroit, Michigan. Dr. Shen is continuing her research at RIA. Prenatal ethanol (alcohol) exposure has profound effects on midbrain dopamine systems,” according to RIA scientist Roh-Yu Shen, Ph.D. Shen and colleagues Hannigan and Kapatos examined alcohol use during pregnancy to understand the changes in the electrical activity of dopamine neurons in adulthood. Background Info Millions and millions of nerve cells in the brain – neurons – communicate with each other by means of chemical messengers called neurotransmitters. Thousands of these messages are sent moment-to-moment throughout the day. Dopamine is one of these neurotransmitters and it has been studied by scientists for more than four decades. Dopamine is responsible for regulating motor function, pleasure/reward, and focus of attention. It has been called the “feel-good” chemical because addictive substances like drugs, alcohol, and nicotine increase the levels of dopamine in the brain (and thereby the feeling of pleasure/reward). Insufficient dopamine levels in the brain have been suggested as the cause of Parkinson’s disease, craving for drugs, and attention deficit/hyperactivity disorder. We now know that alcohol exposure during pregnancy can lead to profound abnormalities in fetal brain development which contributes to fetal alcohol syndrome. The behavioral symptoms in fetal alcohol syndrome include mental retardation, impairment in visual-motor coordination, hyperactivity, and attention problems. Among these, attention and hyperactivity problems may be caused by abnormalities in the dopamine system. Alcohol Use During Pregnancy According to Shen, “Spontaneous activity of dopamine neurons can lead to the release of dopamine and help the brain focus attention. Fetal alcohol exposure could impair attention, possibly by decreasing the activity of dopamine neurons in the midbrain area.” “Drugs like Ritalin are often prescribed for children with attention deficit/hyperactivity disorders,” she stated. “Stimulants like Ritalin increase the ability to focus by restoring dopamine function in the brain. Ritalin is one of the amphetamine-like stimulants that are effective in treating attention deficit and has been reported to be effective in treating attention problems in children with fetal alcohol syndrome. It is possible that the effect of Ritalin in this case is through restoring the spontaneous activity in dopamine neurons.” This Study Shen and her colleagues administered alcohol to pregnant rats and then studied the effects of prenatal alcohol exposure on dopamine neurons in the midbrain area of the offspring. Shen said, “In normal rat brains, about 50 percent of the dopamine neurons are spontaneously active. Human brains operate on a similar principle. Higher levels of spontaneous activity in dopamine neurons can release more dopamine and allow the brain to focus more, whereas lower levels of activity in dopamine neurons may be related to an inability to focus with or without increased hyperactivity.” The Results Animal studies have previously shown that prenatal ethanol exposure causes a “hypofunction” or lessening in dopamine neurotransmission. This hypofunction of the dopamine system may be related to the cause of attention and hyperactivity problems often reported in children with fetal alcohol effects or fetal alcohol syndrome. Shen, Hannigan, and Kapatos found that alcohol exposure impacts the midbrain dopamine system of the rat through adulthood. Their research demonstrated that prenatal alcohol exposure significantly reduced the number of spontaneously active dopamine neurons in both young and middle-aged male offspring. This suggests a long-term effect of prenatal alcohol exposure on the brain’s ability to focus attention. Discussion The results of this study indicate that the prenatal ethanol exposure-induced reduction in the spontaneous activity of midbrain dopamine neurons is a persistent phenomenon that lasts into adulthood. Therefore, rather than a developmental delay, prenatal ethanol exposure induces permanent changes in brain dopamine function. No evidence was found for a loss of dopamine cell bodies in the midbrain. Thus, the reduction in the spontaneous activity in dopamine neurons is most likely the result of impairment in action potential generation. Experimental results suggest that this impairment renders neurons incapable of firing action potentials. Interestingly, scientists found certain pharmacological agents can reverse the decreased activity of dopamine neurons and this may be the reason why Ritalin is effective in treating the attention problems seen in children with fetal alcohol syndrome. “Understanding how fetal alcohol exposure impacts the brain dopamine system can, at the very least,” Shen said, “allow us to understand the cellular mechanisms of changes in the brain that might cause attention and hyperactivity problems. This can lead us to develop tools that may improve our treatment strategies.” Much of the current treatment for attention deficits is based on trial and error, according to Shen, rather than on basic science. Her work begins to supply the science for both future research and treatment. Shen wants to focus her ongoing work on midbrain dopamine neurons in order to better understand the reasons for diminished spontaneous activity. “We would like people to understand that not only alcohol exposure, but cocaine exposure, and even lead exposure during pregnancy or early postnatal development can also decrease the activity of dopamine neurons. The decreased activity could be one of the causes of attention-deficit disorder and hyperactivity. We believe reducing the exposure to these substances during early development has the potential of decreasing the occurrence of these problems.” Clinical Implications: It is important to understand the prenatal alcohol exposure affects brain function in adulthood as well as during early development. Educating clients that one of the possible causes of attention-deficit and hyperactivity disorder might be exposure to alcohol, cocaine, or lead during prenatal or early postnatal development may help prevent these disorders from occurring. References Druse, M. J. (1992). Effects of in utero ethanol exposure on the development of neurotransmitter systems. In M. W. Miller (Ed.), Development of the central nervous system: Effects of alcohol and opiates (pp. 139-167). New York: Wiley. Osterheld, J. R., Kofoed, L., Tervo, R., Fogas B., Wilson, A., Fiechtner, H. (1998). Effectiveness of methylphenidate in Native American children with fetal alcohol syndrome and attention deficit hyperactivity disorder: A control pilot study. Journal of Child Adolescence Psychopharmacology, 8, 39-48. Streissguth, A. P., Aase, J. M., Clarren, S. K., Randels, S. P. LaDue, R. A., Smith, D. F. (1991). Fetal alcohol syndrome in adolescents and adults. Journal of American Medical Association, 265, 1961-1967. Article 2

William R. Greiner, President

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