News and Publications

Laboratory of Clinical Neurophysiology and San Diego Native American Project

C.L. Ehlers, D. Braca, P. Duro, C. Garcia-Andrade, D. Gilder, J. Havstad, S. Lopez, E. Phillips, E. Riley, S. Robeck, C. Slawecki, C. Somes, A. Veltrano, T. Wall, V. Wong

Our research program is dedicated to understanding genetically mediated factors involved in the development of alcoholism and the toxic consequences of alcohol abuse. The importance of genetics in the vulnerability to alcoholism is supported by evidence from family, twin, and adoption studies. Individual sensitivity to alcohol has been proposed as one of the best understood inherited factors that affect the likelihood of drinking and mediate disposition for the development of alcoholism.

Our findings predict that people at higher genetic risk for alcoholism are less sensitive to the effects of alcohol. Support for this theory is provided by results that compared responses in subjects with and without a family history of alcoholism. At moderate doses of alcohol, both groups attained equivalent blood alcohol concentrations, but subjects with a family history of alcoholism rated themselves as significantly less intoxicated than the other subjects did and had CNS signs that indicated a less depressant effect of alcohol. Additional support for this theory is provided by our studies in persons of Asian heritage, who, as a whole, have significantly lower rates of alcoholism than do non-Asians. Asian subjects with mutations in the gene for aldehyde dehydrogenase, an enzyme that breaks down alcohol and that is deficient in 40% of Asians, had more intense, although not necessarily more adverse, responses to alcohol than did Asians without this mutation.

In parallel studies, we have been investigating the response to alcohol in Native American subjects. Compared with other ethnic groups, some tribes of Native Americans have higher rates of alcohol abuse and alcohol dependence. A once popular hypothesis, the firewater myth, proposes that Native Americans are constitutionally unable to handle alcohol. Although the idea that Native Americans are more sensitive to the effects of alcohol has been propagated for more than 3 centuries, it has not been previously directly investigated in the laboratory.

Native American men as a group had markedly diminished objective and subjective responses to ingestion of alcohol, a finding similar to what we found in Caucasian subjects at high risk for alcoholism. In response to a challenge dose of alcohol, Native American men had no changes in cardiovascular status and no increases in stress hormones, findings commonly seen in Asian and Caucasian subjects. In addition, the Native American subjects had fewer CNS signs of the depressant effects of alcohol. Finally, we found that a small proportion of Native American men have variations in the gene for an isozyme of alcohol dehydrogenase. Although this enzymatic difference most likely has no effect on the development of alcoholism, it could make the subjects at greater risk for liver disease if they choose to drink. These findings clearly indicate that biological factors play a role in the increased risk for development of alcoholism in Native American men.

This probable genetic mediation of differences in response to drinking led us to investigate what mechanisms in the CNS might regulate alcohol intoxication and dependence. Therefore, we have studied both animal models of alcohol dependence and rats genetically selected and bred for alcohol-preferring and alcohol-nonpreferring drinking behaviors. Using electrophysiologic measures, we found that, like sons of alcoholics, rats that prefer to drink alcohol have differences in electroencephalographic patterns and show fewer intoxicating and more activating effects of alcohol than the alcohol-nonpreferring rats do.

The alcohol-preferring rats also have significantly lower levels of the neuromodulators corticotropin releasing factor and neuropeptide Y in several areas of the brain. Because these neurohormones are intimately involved in the stress response, these studies suggest that the genetic mediation of alcohol-seeking behavior and the response to alcohol in these animals may involve physiologic differences in responses to "stressors."

We also found that neuropeptide Y, when injected into the brain, is a powerful anxiety-reducing compound and can mimic many of the effects of alcohol, as well as block the effects of corticotropin releasing factor. Alcohol-preferring rats have a significantly more intense response to corticotropin releasing factor than alcohol-nonpreferring rats do and have a less intense response to neuropeptide Y injected into the brain. These findings suggest that the biological basis of vulnerability to alcohol-seeking behavior may involve an imbalance between neurohormones involved in the control of stress and anxiety.

One of the tragic consequences of alcohol abuse during pregnancy can be development of the fetal alcohol syndrome (FAS). FAS is characterized by the presence of several birth defects, including growth retardation, craniofacial abnormalities, and CNS disorders. Delineation of the mechanisms that underlie the development of FAS has been hampered by the lack of an objective clinical test. We developed a clinical battery of tests to characterize behavior, temperament, and neurophysiology in children with this syndrome.

We also studied children who were exposed to large amounts of alcohol during pregnancy but do not have the changes in facial structure characteristic of FAS. In addition, the clinical profile of children with prenatal exposure to alcohol (PEA) differs somewhat from the profile of children with FAS. Children with PEA do not have electroencephalographic abnormalities but do have deficits in the ability to pay attention and respond appropriately to stimuli as measured by event-related potentials. Both groups of children have severe behavioral problems.

These studies provide support for a set of objective clinical tests that can be used to distinguish children with FAS or PEA from control subjects (children without FAS or PEA) and from other children with cognitive disorders. The findings not only will facilitate the detection of children with FAS or PEA but also may help in understanding which regions of the brain may be particularly vulnerable to alcohol abuse and dependence during pregnancy.

How does alcohol act on the brain to produce intoxicating effects? One hypothesis is that alcohol may partially dissolve in the fatty layers that surround the outside of nerve cells (membrane lipids). Recent hypotheses have shifted from a focus on lipids to include a direct interaction with specific receptor proteins that have a "pocket" that binds or traps molecules such as alcohol.

Although studies have shown that alcohol affects both lipids and receptor proteins, the amount of alcohol required to produce the effects is several times larger than the amount needed to be legally drunk. We proposed that ethanol may act on lipid and proteins in the brain not by noticeably altering the function of these molecules but by perhaps making them "wobble" in such a way that a level of unpredictability or "noise" is added to cellular interactions in the brain. To assess this hypothesis, we used a series of measures derived from chaos theory to measure the effects of low amounts of alcohol on brain and behavior. The findings of the study were consistent with the hypothesis that alcohol does act by introducing a level of unpredictability in neuronal processing.

PUBLICATIONS

Ehlers, C.L., Garcia-Andrade, C., Wall, T., Cloutier, D., Phillips, E. Encephalographic responses to alcohol challenge in Native American Mission Indians. Biol. Psychiatry, in press.

Ehlers, C.L., Garcia-Andrade, C., Wall, T.L., Sobel, D.F., Phillips, E. Determinants of P3 amplitude and response to alcohol in Native American Mission Indians. Neuropsychopharmacology 18:282, 1998.

Ehlers, C.L., Havstad, J., Pritchard, D., Theiler, J. Low doses of ethanol reduce evidence for nonlinear structure in brain activity. J. Neurosci., in press.

Ehlers, C.L., Kupfer, D.J., Buysse, D.J., Cluss, P.A., Miewald, J.M., Bisson, E.F., Grochocinski, V.J. The Pittsburgh study of normal sleep in young adults: Focus on the relationship between waking and sleeping EEG spectral patterns. Electroencephalogr. Clin. Neurophysiol., in press.

Ehlers, C.L., Li, T.-K., Lumeng, L., Hwang, B.H., Somes, C., Jimenez, P., Mathé, A.A. Neuropeptide Y (NPY) levels in ethanol-naive alcohol preferring and non-preferring rats and in Wistars following ethanol exposure. Alcohol Clin. Exp. Res., in press.

Ehlers, C.L., Somes, C., Cloutier, D. Are some of the effects of ethanol mediated through NPY? Psychopharmacology, in press.

Ehlers, C.L., Somes, C., Lopez, A.L., Robledo, P. Long latency event-related potentials in rats: Response of amygdala, nucleus accumbens, dorsal hippocampus and frontal cortex to changes in reward characteristics of conditioned stimuli. Brain Res. 780:138, 1998.

Orozco, S., Ehlers, C.L. Gender differences in electrophysiological responses to facial stimuli. Biol. Psychiatry, in press.

Seifritz, E., Klemfuss, H., Britton, D.T., Ehlers, C.L. Corticotropin-releasing hormone: A role in circadian regulation. Pharmacol. Biochem. Behav., in press.