Dec. 8, 1998 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.
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.
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