Blocking selected neurotransmitter activity may decrease alcohol consumption

• Neuropeptide Y (NPY) is a neurotransmitter that is integral to neurobiological functions such as anxiety, pain, memory and feeding behaviors.

• Researchers have found that a compound that blocks NPY activity decreases both the onset as well as the repetition of alcohol consumption.
• These findings have important implications for the treatment of both alcohol abuse and dependence.

Peptides are a class of neurotransmitters, chemicals used by brain cells to communicate with each other. Neuropeptide Y (NPY) is the most abundant and widely distributed peptide, and is involved in a variety of neurobiological functions, including anxiety, pain, memory, and feeding behavior. Although previous animal research has implicated NPY systems in alcohol abuse and alcoholism, findings published in the December issue of Alcoholism: Clinical & Experimental Research are the first to show that a compound that blocks NPY activity may be useful for alcohol treatment.

“NPY is the most potent stimulant of feeding behavior known,” explained Clyde W. Hodge, associate professor in the departments of psychiatry and pharmacology at the University of North Carolina at Chapel Hill and corresponding author for the study. “For example, the primary brain region involved in control of eating is the hypothalamus. Animal studies have shown that repeated treatment of the hypothalamus with NPY produces dietary obesity in otherwise normal rats. We suspect that alcohol may usurp brain systems that evolved to perform other functions, such as eating, because these neural systems evolved long before humans discovered alcoholic beverages. Alcohol and drug abuse, therefore, can be considered disorders of consumption.”

“Since NPY is a signal molecule, it produces its effects via several NPY receptors in the brain, such as the NPY-Y5 receptors,” added Subhash C. Pandey, associate professor and director of Neuroscience Alcoholism Research in the department of psychiatry at the University of Illinois at Chicago. “This research suggests that alcohol-preferring mice may have higher levels of NPY-Y5 receptors in the brain. Other research suggests that these mice have lower NPY levels in the brain area involved in reward of alcohol drinking. It is also possible that both lower NPY levels and higher NPY-Y5 receptors in the brain may be associated with the excessive alcohol drinking behaviors of these mice.”

This study uses alcohol-preferring mice called C57BL/6 to examine the effects of the NPY-Y5 receptor antagonist L-152,804 on the onset and maintenance of alcohol self-administration.

“Most of the known compounds that target NPY receptors do not cross the blood-brain barrier,” said Hodge. “L-152,804, however, is a novel compound that was recently shown to both cross the blood-brain barrier and block NPY-Y5 receptors.”

Researchers housed 59 male C57BL/6J mice in standard Plexiglas cages (4 per cage) with food and water always available. Mice were trained to self-administer either alcohol (10% v/v) or water during 16-hour sessions. After four months, the mice were injected systemically with L-152,804 (0, 10, 30 or 60 mg/kg) prior to the sessions.

Results indicate that not only does L-152,804 delay the onset of alcohol self-administration, which is considered an index of relapse potential, but it also seems to reduce the reinforcing, or rewarding, effects of alcohol.

“The process by which drug self-administration behavior becomes repetitive is called positive reinforcement,” said Hodge. “It reflects the tendency of all animals, human and non-human, to repeat responses that produce a desired outcome. In general, this process functions to sustain behavior that is essential to the individual or species, such as eating, drinking or reproduction. In this particular case, L-152,804 appeared to block the reinforcing effects of alcohol. When taken together, these results suggest that L-152,804 might reduce the motivation to start drinking as well as decrease the amount of alcohol consumed. Thus, L-152,804 might make relapse less likely and possibly dampen its consequences.

Both Hodge and Pandey said these results have clear implications for the medical management of alcohol abuse and alcoholism.

“If these studies are replicable and consistently produce findings that alcohol preference and dependence are associated with increased NPY-Y5 receptors in the brain,” said Pandey, “then blocking these receptors with L-152, 804 may be useful in treating alcoholism. Furthermore, since this receptor antagonist is able to delay the onset of alcohol-drinking behaviors in alcohol-preferring mice, it also has potential in preventing relapse to alcohol abuse.”

“Approved medications for alcoholism such as naltrexone,” added Hodge, “may help prevent relapse but do not decrease drinking by chronic alcoholics who are actively drinking. L-152,804 has the potential to both prevent relapse and decrease active drinking. When you also consider the fact that L-152,804 can be administered orally, we believe that medications that block NPY actions at its receptors have great potential for the medical management of alcoholism.”

Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper included Jason P. Schroeder and Kimberly A. Iller of the Department of Psychiatry and Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the State of California, and the Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill.