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Volume 18, Number 3, September 2007
Thiele Laboratory Neuropeptide Research Reveals
Therapeutic Targets for Alcoholism
Recent years have witnessed an explosion of research into the functions of neuropeptides—compounds that are composed of at least two amino acids linked by peptide bonds and that are found in neural tissue. Neuropeptides have been identified throughout the animal kingdom. Approximately 100 of them have been found in the mammalian brain. Neuropeptides appear to mediate a vast array of functions in both health and disease. Research suggests that neuropeptides are important modulators of phenomena as various as the foraging behavior of honeybees and the “runner’s high” that sustains marathoners through long distances. Neuropeptides have also been implicated as contributing to pathologic conditions including diabetes, obesity, Alzheimer’s disease, and drug addiction.
Dr. Todd Thiele, associate professor and director of research services in the department of psychology and member of the curriculum of neurobiology and the Bowles Center for Alcohol Studies at UNC, is particularly interested in how neuropeptides contribute to alcohol abuse and alcoholism. A quietly intense scientist, Thiele is known for his systematic and thorough approach to tackling tough scientific questions. In a multipronged program of studies, Thiele has elucidated the role of several neuropeptides in alcohol consumption and has identified potential biological targets for treatments for alcohol abuse. Thiele’s work on alcohol and neuropeptides initially focused on neuropeptide Y, a signaling protein widely distributed throughout the brain. He found that mice genetically altered to be deficient in this neuropeptide drank much more alcohol than mice with normal neuropeptide Y levels (wild-type mice) and were more resistant to the sedative and hypnotic effects of alcohol. Conversely, mice genetically altered so that they overproduced neuropeptide Y drank less alcohol and were more sensitive to alcohol’s sedative and hypnotic effects than mice with normal neuropeptide Y levels. Thiele’s masterful demonstration of an inverse relationship between neuropeptide Y levels and alcohol consumption or resistance was published in the prestigious scientific journal Nature.
Thiele Lab (Left to Right): Dayna Hayes, Todd Thiele, PhD, Angela Sparrow, Emily Lowery, Montserrat Navarro, PhD, Lorraine Ko, Ping He.
Thiele next turned to the question of how neuropeptide Y affects the brain to cause changes in alcohol consumption. Neuropeptide Y binds to several receptor subtypes found on brain cell surfaces to cause changes in cell function. In a series of studies with mice genetically altered to lack specific receptor subtypes, Thiele identified the receptor subtypes that appear to be responsible for neuropeptide Y effects on voluntary alcohol consumption. Mice lacking the Y1 receptor or the Y2 receptor, but not the Y5 receptor, showed altered alcohol consumption compared with wild-type mice.
Having shown that neuropeptide Y modulates voluntary alcohol consumption and having identified the receptors involved, Thiele next sought to address the specific brain regions important in mediating neuropeptide Y effects. Thiele and graduate student Dayna Hayes assessed neuropeptide Y amounts in the brains of two strains of mice: one that naturally drinks large amounts of alcohol and another that avoids alcohol. They found that the high-alcohol-drinking mice compared with the alcohol-avoiding mice had substantially reduced levels of neuropeptide Y in specific brain regions including the shell of the nucleus accumbens, the basolateral amygdala, and the central nucleus of the amygdala (Figure). These results are consistent with the possibility that low neuropeptide Y levels in these regions predispose the high-drinking mice to increased alcohol consumption. To further explore this possibility, Thiele administered substances (viral vectors) that cause secretion of neuropeptide Y into specific brain regions and examined subsequent effects on alcohol consumption in mice. Administration of a viral vector causing neuropeptide Y secretion within the central nucleus of the amygdala in high-alcohol-drinking mice significantly reduced alcohol consumption relative to that in high-alcohol-drinking mice who were not administered the viral vector.
Thiele and his laboratory extended their studies of neuropeptide Y to assess its involvement in the alcohol withdrawal syndrome, which is manifested by neurologic symptoms such as difficulty concentrating, anxiety, and hallucinations and by motor symptoms ranging from muscle tremors to convulsions. The alco-holic’s con-tinued drinking is motivated in part by the need to prevent or alleviate these symptoms. Knowing that neuropeptide Y is involved in alcohol drinking as well as emotional responses, Thiele hypothesized that neuropeptide Y might mediate the anxiety that occurs during the alcohol withdrawal syndrome. With graduate students Dennis Sparta and Jon Free and fellow Bowles Center for Alcohol Studies scientists Drs. George Breese and Darin Knapp, Thiele found that mice deficient in neuropeptide Y compared with mice with normal levels of neuropeptide Y indeed show heightened withdrawal-associated anxiety as measured by established laboratory tests of emotionality. These data suggest that neuropeptide Y may modulate alcohol withdrawal-associated anxiety.
Thiele and his laboratory have also explored the role of another group of neuropeptides—the melanocortins—in alcohol consumption. With colleague Dr. Montserrat Navarro and others at the Bowles Center, Thiele explored the roles of specific cellular receptors (the melanocortin-3 and melanocortin-4 receptors) in alcohol consumption. In one experiment, high-alcohol-drinking mice were found to reduce their drinking after infusion of an agent that activates melanocortin-4 receptors and to increase their drinking after infusion of an agent that shuts down melanocortin-4 receptors. Considered in the context of other data, the results suggest that melanocortin receptor signaling modulates voluntary alcohol consumption and high-light the promise of compounds affecting melanocortin receptors for treating alcohol-abuse disorders.
Thiele and his colleagues have also provided evidence of therapeutic promise of compounds that affect corticotropin releasing factor, another neuropeptide that is widely distributed in the brain. They have recently found that treating high-alcohol-drinking mice with a drug that shuts off a specific corticotropin releasing factor receptor (the corticotropin releasing factor-1 receptor) prevents the surge in alcohol drinking that occurs after a period of alcohol deprivation in these animals. In another study, they showed that administration of a drug that shuts off the corticotropin releasing factor-1 receptor protected mice from the increase in alcohol drinking caused by stress.
Figure: Neuropeptide Y immunofluorescence in the amygdala. Brain sections from high-alcohol-drinking mice (C57BL/6J) (Panel A) and alcohol-avoiding mice (DBA/2J) (Panel B). Panels C and D show quantification of immunofluorescence (reflecting levels of neuropeptide Y) in the central nucleus of the amygdala and the basolateral amygdala. From Hayes et al. Alcohol Clin Exp Res 2005;29:721-729.
When neuropeptides bind to receptors on brain cells, they initiate a cascade of events that alter cellular function and, ultimately, determine how these cells will affect behavior. One of the key steps in this cascade of events is alteration of the activity of the intracellular enzyme protein kinase A. All of the neuropeptides that Thiele and his colleagues have shown to be important in alcohol effects—neuropeptide Y, melanocortins, and corticotropin releasing factor—impact protein kinase A activity. Possibly, the protein kinase A signaling pathway constitutes a shared substrate by which these neuropeptides affect alcohol consumption. In support of this possibility, Thiele found that mice genetically engineered to lack a structural component of protein kinase A (i.e., the regulatory II b subunit) drank significantly more alcohol than normal mice with functional regulatory II b subunits. In addition, mice lacking the regulatory II b subunit were less sensitive to the sedative effects of alcohol than normal mice but more sensitive to the locomotor stimulant effects of alcohol and to alcohol-induced locomotor sensitization (in which the locomotor response to alcohol is increased with repeated administration of alcohol). These results suggest that the regulatory II b subunit of protein kinase A contributes to regulation of alcohol intake and intoxication. In other research, Thiele and his colleagues provided evidence suggesting that, while the regulatory II b subunit is important in alcohol consumption, it is not a key mediator of pre-consummatory behavior directed at obtaining alcohol.
Thiele’s productivity and systematic approach to posing and answering scientific questions have yielded tremendous benefits to the alcohol field. “Our work has provided a better understanding of how neuropeptides modulate alcohol ingestion,” says Thiele. “The data point to important roles of several neuropeptides in alcohol drinking and reveal several potential targets for development of therapeutic approaches for alcohol abuse and relapse behaviors.”