Relaxed mice may provide clues for treating anxiety

October 02, 2002

Your heart is racing, you're sweating, trembling, feel exhausted and cannot breathe - for over 20 million Americans who face chronic and excessive anxiety each day, these physical reactions to real or imagined danger are well known. Prescription anxiolytics (anxiety-reducing medications), such as clonazepam (Klonopin), alprazolan (Xanax) and lorazepam (Ativan) have been widely employed in the treatment of anxiety disorders to relieve these physical symptoms while other forms of behavioral therapy proceed, however their long-term use is discouraged due to their somewhat addictive potential and sedating side effects. A study reported in the October 1 issue of the Journal of Clinical Investigation (JCI) by Dr. Robert Messing and colleagues from the Ernest Gallo Clinic and Research Center at the University of California, San Francisco, reveals that mice lacking a form of the enzyme protein kinase C (PKCe) are supersensitive to their brain's own calming neurosteroids and exhibit reduced anxiety. The authors suggest that inhibitors of PKCe may be useful in treating anxiety.

Severe and excessive anxiety is associated with irregular levels of neurotransmitters in the brain. These chemicals ferry signals between nerve endings and regulate the activity of nerve cells. An inhibitory agent within the central nervous system, gamma aminobutyric acid (or GABA), is the most important blocker of this communication between neurons and helps control nerve cells from firing too fast. The GABAA receptor forms a closed channel that is triggered to open upon the binding of GABA. A rush of chloride ions through the open channel into the cell inhibits the release of neurotransmitters. In this way, drugs such as barbiturates and the benzodiazepines mentioned above decrease anxiety, induce sleep and even anesthesia.

Earlier studies by this group reveal that mice lacking the gene for PKCe have an increased sensitivity to alcohol, benzodiazepines and barbiturates. These observations have now been extended to include a supersensitivity to the brain's own endogenous neurosteroids that routinely regulate neuron activity. In mice lacking PKCe, the interaction of endogenous neurostreroids with the GABAA receptor (in the presence of GABA) caused the channel to open, and the significant increase in chloride ions rushing into the cell had a greater effect on the inhibition of neurotransmission and significantly reduced anxious behavior in these mice. "Given that enhancers of GABAA receptor activity have proven clinically problematic, the finding that PKCe deficiency yields anxiolytic-like results is promising and it is attractive to imagine that PKCe blockade would result in anxiolysis by making our brains more sensitive to our own endogenous anxiolytics" noted Dr. Joshua Gordon of the Center for Neurobiology and Behavior at New York's Columbia University in his accompanying Commentary in the JCI. Further research is required to define the mechanisms by which PKCe and neurosteroids modulate GABA receptors but these results suggest that PKCe is a possible target for the development of novel therapeutics for the treatment of anxiety.

Dr. Robert O. Messing
Ernest Gallo Clinic and Research Center
University of California, San Francisco
5858 Horton St., Suite 200
Emeryville, CA 94608
TEL: 510-985-3950
FAX: 510-985-3101

Dr. Joshua A. Gordon
Center for Neurobiology and Behavior
Columbia University / New York State Psychiatric Institute
10051 Riverside Drive, Unit 87
New York, NY 10032
TEL: 212-543-5309
FAX: 212-543-5074

JCI Journals

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