http://www.jci.org/c...ourcetype=HWCIThttp://www.nih.gov/n...5/niaaa-03b.htmNational Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Researchers Shed Light on Anxiety and Alcohol Intake
Scientists have identified a brain mechanism in rats that may play a central role in regulating anxiety and alcohol-drinking. The finding, by researchers supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH), could provide important clues about the neurobiology of alcohol-drinking behaviors in humans. A report of the study appears in the October 3, 2005 issue of the Journal of Clinical Investigation.
“This is an intriguing finding,” notes NIAAA Director Ting-Kai Li, M.D. “These experiments, conducted in rats selectively bred to have a high affinity for alcohol, help us address questions about the potential role that anxiety might play in human alcoholism. These molecular studies also may reveal potential targets for therapy of anxiety and alcoholism.”
Some researchers have suggested that high levels of anxiety may predispose some individuals to becoming alcoholic.
Researchers led by Subhash C. Pandey, Ph.D., Associate Professor and director of neuroscience alcoholism research in the Department of Psychiatry at the University of Illinois and Jesse Brown VA Medical Center in Chicago, found that “P” rats, a strain bred to prefer alcohol, showed more anxiety-like behaviors and drank more alcohol, than non alcohol-preferring “NP” rats. They measured anxiety in the rats with an apparatus known as an elevated plus-maze, which consists of two open arms and two closed arms connected to a central platform. Anxiety is gauged as a function of the amount of time a rat spends in the closed versus the open arms of the maze during a 5-minute testing period — the greater an animal’s level of anxiety, the less open-arm activity it displays.
Dr. Pandey and his colleagues also found that levels of CREB, a protein involved in a variety of brain functions, were lower in certain brain areas of P rats compared with NP rats. Levels of neuropeptide Y (NPY), a molecule that regulates the function of several neurotransmitters and is known to play a role in anxiety and alcohol-drinking behaviors, also were lower in P rats. One function of CREB is to regulate the production of NPY.
“Compared to NP rats, levels of CREB and NPY were innately lower in the central amygdala and medial amygdala of P rats,” explains Dr. Pandey, “brain areas which play a crucial role in anxiety behaviors and which have been shown previously to be involved in rewarding, reinforcing, and motivational aspects of alcohol drinking behaviors. And turning off CREB function in the central amygdala of NP rats makes them look like P rats — more anxious and thus more likely to drink.”
Alcohol intake reduced anxiety-like behaviors in the P rats, an effect that was associated with increased CREB function and NPY production in the central and medial amygdala. And by administering compounds that promote CREB function and NPY production in the central amygdala, researchers were able to reduce anxiety — and alcohol intake — in P rats. On the other hand, by disrupting CREB function (and the concomitant NPY production) in the central amygdala of NP rats, the researchers were able to provoke anxiety-like behavior and promote alcohol intake in those animals.
Dr. Pandey and his colleagues proposed that decreased CREB-dependent NPY production in the central amygdala might be a pre-existing condition for anxiety and alcohol-drinking behaviors.
“Our findings implicate this pathway in genetic predisposition to high anxiety and alcohol-drinking behaviors of P rats,” says Dr. Pandey. “Future studies should explore the relationship of other CREB-related compounds to these phenomena in P rats or other animal models.”
The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of the U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at www.niaaa.nih.gov.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.
The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice.
Karlsson RM, Choe JS, Cameron HA, Thorsell A, Crawley JN, Holmes A, Heilig M.
Laboratory of Clinical and Translational Studies, NIH, National Institute of Alcohol Abuse and Alcoholism, NIH, 10 Center Drive, 1-15330, Bethesda, MD, 20892-1375, USA.
RATIONALE: Neuropeptide Y (NPY) is implicated in the pathophysiology of affective illness. Multiple receptor subtypes (Y1R, Y2R, and Y5R) have been suggested to contribute to NPY's effects on rodent anxiety and depression-related behaviors. OBJECTIVES: To further elucidate the role of Y1R in (1) NPY's anxiolytic-like effects and (2) fluoxetine's antidepressant-like and neurogenesis-inducing effects. METHODS: Mice lacking Y1R were assessed for spontaneous anxiety-like behavior (open field, elevated plus-maze, and light/dark exploration test) and Pavlovian fear conditioning, and for the anxiolytic-like effects of intracerebroventricularly (icv)-administrated NPY (elevated plus-maze). Next, Y1R -/- were assessed for the antidepressant-like effects of acute fluoxetine in the forced swim test and chronic fluoxetine in the novelty-induced hypophagia test, as well as for chronic fluoxetine-induced hippocampal neurogenesis. RESULTS: Y1R -/- exhibited largely normal baseline behavior as compared to +/+ littermate controls. Intraventricular administration of NPY in Y1R -/- mice failed to produce the normal anxiolytic-like effect in the elevated plus-maze test seen in +/+ mice. Y1R mutant mice showed higher immobility in the forced swim test and longer latencies in the novelty-induced hypophagia test. In addition, Y1R -/- mice responded normally to the acute and chronic effects of fluoxetine treatment in the forced swim test and the novelty-induced hypophagia test, respectively, as well as increased neuronal precursor cell proliferation in the hippocampus. CONCLUSIONS: These data demonstrate that Y1R is necessary for the anxiolytic-like effects of icv NPY, but not for the antidepressant-like or neurogenesis-inducing effects of fluoxetine. The present study supports targeting Y1R as a novel therapeutic target for anxiety disorders.
PMID: 17891380 [PubMed - as supplied by publisher]
NPY Y1R agonist might work.
