Featured Research

from universities, journals, and other organizations

Genetically Engineered Mice Exhibit Anxiety, Offering Insight Into Role Of Serotonin In Brain

Date:
December 8, 1998
Source:
University Of California, San Francisco
Summary:
Researchers led by a UC San Francisco investigator have genetically altered the serotonin brain system of mice, producing animals that exhibit anxiety, thereby offering an important new model for exploring the way in which the serotonin brain system contributes to anxiety in humans.

Researchers led by a UC San Francisco investigator have genetically altered the serotonin brain system of mice, producing animals that exhibit anxiety, thereby offering an important new model for exploring the way in which the serotonin brain system contributes to anxiety in humans.

Related Articles


The model, reported in the December 7 issue of Proceedings of the National Academy of Science, could help researchers come up with more refined targets for psychiatric drugs. It also could serve as a model for examining inherited personality disorders involving anxiety, the researchers said. Overall, the model provides an important inroad for exploring the highly elaborate, inscrutable serotonin system, which regulates most, if not all, complex behaviors.

Serotonin is one of the brain's key neurotransmitters, which are signaling molecules that transmit chemical messages between brain cells, or neurons. The molecule communicates its messages through interactions with at least 14 distinct types of serotonin receptors, located on the surface of various types of nerve cells in the brain.

In most people, the neural system manages to maintain a normal balance of serotonin activity. In some, however, activity is either abnormally heightened or depressed in any number of different neural pathways. The type of impact serotonin has on the nervous system is determined by its success, or lack thereof, in reaching its target receptors, and the response that these receptors have to the neurotransmitter--either stimulating or inhibiting its activity.

While unusually elevated or inhibited serotonin activity has been implicated in many psychiatric disorders, scientists are unclear about the relative contribution of the various receptor subtypes to the regulation of particular behaviors. "It may be that the set of serotonin receptors regulating one type of behavior, such as feeding, differs from those controlling other responses, such as anxiety, depression and aggression," said the senior author of the study, Laurence H. Tecott, PhD, a MD, a professor of psychiatry at UCSF.

It does appear that elevated serotonin activity is associated with anxiety, and reduced activity with depression, but most psychiatric drugs work unspecifically on all 14 receptor subtypes, revealing little about the relative contributions of each, he said. (For example, serotonin "reuptake blockers," such as Prozac, used to treat depression and a variety of anxiety disorders, enhance the action of serotonin, but do so unspecifically by altering the activation of all serotonin receptor subtypes.)

Such lack of specificity foils attempts to use these drugs as probes into the individual contributions of various receptors. And this limitation, in turn, makes it difficult to fine-tune drugs to the appropriate receptors, which could lead to drugs that avoid side effects.

"If we understood which of the serotonin receptor subtypes contributed to these antidepressant and anxiety-reducing effects, then we might be able to develop more selective drugs with improved effectiveness and fewer side effects," said Tecott.

The mouse model created by Tecott and colleagues at UCSF and a researcher at The Scripps Research Institute, offers insight into the contribution of one particular receptor subtype, 5-HT-1A, to serotonin-mediated anxiety and depression.

The 5-HT-1A receptor inhibits serotonin activity--when the chemical latches onto it, the receptor stops its action--and is believed to be one of the principal inhibitory receptors of the serotonin system.

The researchers reasoned, and ultimately demonstrated, that if the receptor is eliminated altogether, the serotonin system should be disinhibited, causing hyperactive serotonergic activity. They "inactivated" the gene for the 5-HT-1A receptor in a group of mice, and then compared their behavior to that of their normal siblings. The results, said Tecott, were "dramatic."

In three tests designed to test levels of anxiety, the mutant mice displayed behaviors suggesting they were significantly more nervous, skittish and reticent to confront unfamiliar elements in their environment than normal mice. When placed in a brightly lit box, they hugged the walls, opting not to explore the center. When placed in an enclosed area and given the opportunity to roam into an open area, they resisted. And when a novel object--a ping pong ball--was placed in their cage, they appeared more reticent to investigate the object, and spent more time in the relative safety of their nest.

Because antidepressants such as Prozac stimulate 5-HT-1A receptors, among others, the researchers also sought to compare the behavior of the mutant mice with that of mice treated with antidepressant drugs. While they stress that further studies are needed to confirm their observation, their initial findings suggest the mutants were more active than normal mice, an effect that is also produced in mice by antidepressant drugs.

The suggestion that anxious mice could also exhibit anti-depressant-like behaviors is not surprising, said Tecott, as there is substantial evidence that enhanced activity of the serotonin system protects from depression. "Our speculation is that both of these abnormalities--anxiety and anti-depressive responses--can be accounted for by disinhibition of serotonin system activity," said Tecott.

The findings, he said, indicate that an altered serotonin receptor gene can lead to an inherited anxiety disorder, and the mice may be used to study how the serotonin system alters anxiety and, perhaps, depression. It could also be used to test the effectiveness of anxiety reducing, and, perhaps, antidepressant, compounds.

The researchers' next step, said Tecott, is to try to learn more about the neural mechanisms through which the absence of the 5-HT-1A receptor leads to the behavioral abnormalities.

"We'd like to test the hypothesis that the serotonin system is disinhibited in these animals," he said. "If this proves to be the case, then the question is which are the serotonin receptors that are producing the anxiety-like responses? If they are due to increased serotonin system activity, then particular subtypes of serotonin receptors must be contributing to these behaviors."

The study was conducted by Tecott, Lora K. Heisler, PhD, Hung-Min Chu, MD, PhD, Jean A. Danao, BA, and Preetpaul Bajwa, BA, of the UCSF Department of Psychiatry and Center for Neurobiology and Psychiatry at UCSF; Thomas J. Brenann, PhD, now at Deltagen, Inc., and Loren H. Parsons, PhD, of The Scripps Research Institute.

The study was funded by NARSAD, NIDA, the Giannini Foundation, the Veterans Administration, PMRTP and the EJLB Foundation.


Story Source:

The above story is based on materials provided by University Of California, San Francisco. Note: Materials may be edited for content and length.


Cite This Page:

University Of California, San Francisco. "Genetically Engineered Mice Exhibit Anxiety, Offering Insight Into Role Of Serotonin In Brain." ScienceDaily. ScienceDaily, 8 December 1998. <www.sciencedaily.com/releases/1998/12/981208055328.htm>.
University Of California, San Francisco. (1998, December 8). Genetically Engineered Mice Exhibit Anxiety, Offering Insight Into Role Of Serotonin In Brain. ScienceDaily. Retrieved November 1, 2014 from www.sciencedaily.com/releases/1998/12/981208055328.htm
University Of California, San Francisco. "Genetically Engineered Mice Exhibit Anxiety, Offering Insight Into Role Of Serotonin In Brain." ScienceDaily. www.sciencedaily.com/releases/1998/12/981208055328.htm (accessed November 1, 2014).

Share This



More Health & Medicine News

Saturday, November 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Melafind: Spotting Melanoma Without a Biopsy

Melafind: Spotting Melanoma Without a Biopsy

Ivanhoe (Oct. 31, 2014) The MelaFind device is a pain-free way to check suspicious moles for melanoma, without the need for a biopsy. Video provided by Ivanhoe
Powered by NewsLook.com
Battling Multiple Myeloma

Battling Multiple Myeloma

Ivanhoe (Oct. 31, 2014) The answer isn’t always found in new drugs – repurposing an ‘old’ drug that could mean better multiple myeloma treatment, and hope. Video provided by Ivanhoe
Powered by NewsLook.com
Chronic Inflammation and Prostate Cancer

Chronic Inflammation and Prostate Cancer

Ivanhoe (Oct. 31, 2014) New information that is linking chronic inflammation in the prostate and prostate cancer, which may help doctors and patients prevent cancer in the future. Video provided by Ivanhoe
Powered by NewsLook.com
Sickle Cell: Stopping Kids’ Silent Strokes

Sickle Cell: Stopping Kids’ Silent Strokes

Ivanhoe (Oct. 31, 2014) Blood transfusions are proving crucial to young sickle cell patients by helping prevent strokes, even when there is no outward sign of brain injury. Video provided by Ivanhoe
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins