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June 21, 2010
Drug Substitutes for Training to Blunt Fears in Rats
Researchers were able to reduce a conditioned fear in rats by using a drug, mimicking the effect of training. The finding suggests new possibilities for treating anxiety disorders.
Each year anxiety disorders affect an estimated 40 million adults nationwide. Unlike the relatively mild, brief anxiety caused by a stressful event (such as speaking in public or a first date), anxiety disorders cause fearfulness and uncertainty that lasts at least 6 months and can get worse if untreated. While effective therapies are available, an understanding of the molecular mechanisms behind anxiety disorders could lead to better treatments.
Rats serve as a useful model for studying anxiety. Rats freeze when they hear a tone they've been conditioned to associate with an electric shock. This reaction can be reversed by "extinction training" — repeatedly exposing the rats to the tone with no shock. Past studies have shown that extinction training doesn't erase a previously conditioned fear memory. Rather, it creates a new memory associating the tone with safety.
Memory formation involves changes in the connections, or synapses, between neurons. This capacity for change is called synaptic plasticity. A brain region called the infralimbic prefrontal cortex (ILC) is known to be critical for extinction memory in rats. Drugs that block synaptic plasticity impair extinction learning when injected into the ILC, causing rats to continue freezing at high levels after extinction training.
Previous research implicated a protein called brain-derived neurotrophic factor (BDNF) in extinction learning. BDNF is one of a class of proteins known to support the growth and survival of neurons, permitting a learning experience to increase the size and strength of synaptic contacts between neurons.
A research team led by Dr. Gregory Quirk at the University of Puerto Rico School of Medicine set out to study BDNF’s role in extinction learning. They conditioned rats to fear a tone by pairing it with a footshock. They then infused BDNF directly into the ILC. Their work was funded by NIH’s National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS) and National Center for Research Resources (NCRR).
As detailed in the June 4, 2010, issue of Science, infusing BDNF directly into the ILC enhanced extinction training. Even before extinction training, the researchers noticed that freezing was significantly reduced in the BDNF rats. So they repeated their experiments without extinction training and found that the BDNF-infused rats showed little freezing to the tone the next day.
"The surprising finding here is that the drug substituted for extinction training," Quirk says.
BDNF didn't reduce general anxiety or change the animals’ tendency to move around. Further experiments showed that it also didn’t erase the original fear memory.
The researchers compared the brains of various rats after extinction training. Rats with lower BDNF levels were less likely to succeed in extinction training.
"Many lines of evidence implicate BDNF in mental disorders," says NIMH Director Dr. Thomas Insel. "This work supports the idea that medications could be developed to augment the effects of BDNF, providing opportunities for pharmaceutical treatment of post-traumatic stress disorder and other anxiety disorders."