Cells May Provide Target for New Anxiety Medications

November 6, 2008 • Science Update

A specific population of brain cells could provide a target for developing new medications aimed at helping people learn to mute the fears underlying anxiety disorders, according to NIMH-supported scientists.

Background

As a way of modeling anxiety disorders in humans, researchers can train rats to fear a tone by coupling it with a foot shock. If this fear conditioning is followed by repeated exposure of the rats to the tone without any shock, the rats stop "freezing" in fear in response to the tone, a behavioral change called fear extinction. In humans, fear extinction is an important component of treatment for anxiety disorders. Treatment does not eliminate the memory of the fear, but the fear reaction is diminished.

This Study

In this study, the investigators selectively disrupted a specific class of brain cells, or neurons, in the amygdala, a part of the brain involved in emotional learning. Research suggests that these neurons, called intercalated or ITC neurons, may form a relay between centers in the amygdala that process sensory information and shape the fear response.

To examine this possibility, the investigators took advantage of the fact that, in comparison with neighboring neurons, ITC neurons have a rich supply of mu-opioid receptors—sites on the cell surface to which endogenous opiates, a class of brain signaling molecule, bind. By coupling a toxin to a molecule that targets these receptors, the investigators were able to selectively disrupt ITC cells. Eight days later, the rats that had received the toxin were significantly less likely to show the effects of fear extinction than rats whose ITC cells were intact – they were more likely to freeze when encountering the tone, in spite of the training aimed at fear extinction. The outcome was not the result of differences in overall anxiety among the rats; treated rats were as likely to explore new surroundings as untreated.

Significance

Deficits in brain circuits that underlie fear extinction may contribute to human anxiety disorders. With these results, it may be possible to design medications that could enhance the function of ITC cells, and increase the effectiveness of fear extinction therapy for anxiety disorders.

NIMH-supported scientist Denis Paré, Ph.D., and graduate student Ekaterina Likhtik, who also has NIMH support, conducted the study with colleagues at Rutgers State University, Newark, New Jersey. The work was reported in the July 31 issue of the journal Nature.

What's Next

Continuing research will test the details of the cell signaling described here and the potential for using this model as a basis for developing novel treatments.

Reference

Likhtik, E., Popa, D., Apergis-Schoute, J., Fidacaro, G.A., and Pare, D. Amygdala intercalated neurons are required for expression of fear extinction. Nature 2008 Jul 31;454(7204):642-5. PMID: 18615014