Fear-eliminating Drug Works in Rats

Rats that are shocked when they hear a certain tone typically freeze up upon hearing that sound later. A drug injected into their brains can reduce this fear nearly as well as a fear-erasing training method.

The work suggests scientists might be able to develop new types of drugs for the treatment of anxiety disorders, which affect an estimated 40 million adults nationwide every year.  

However, more research is needed to determine whether the results apply to humans experiencing real fear, as opposed to learned fear.

The study was published June 4 in the journal Science.

Freeze response

If a rat learns to associate a sound with an electric shock, the "freeze" response 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.

When this new memory is formed, the brain undergoes changes in the connections, or synapses, between neurons. Drugs that block this so-called synaptic plasticity impair the ability to reform once-fearful memories (extinction learning), when they are injected into a brain region called the infralimbic prefrontal cortex (ILC). The result: Rats continue freezing at high levels even after they are trained to have a "safe memory" of that fearful shock.

Previous research suggested  a protein called brain-derived neurotrophic factor (BDNF) does the opposite by promoting extinction learning. Scientists think this happens because BDNF supports the growth and survival of neurons, permitting learning experiences to make connections between neurons stronger and more prevalent.

To put all these puzzle pieces together, the researchers conditioned rats to fear a tone by pairing it with a foot shock. They then infused BDNF directly into the ILC.

Introducing BDNF directly into the ILC enhanced the rats' ability to relearn a once-feared memory. 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 following day.

"The surprising finding here is that the drug substituted for extinction training," said study researcher Gregory Quirk, at the University of Puerto Rico School of Medicine.

Memories remain

BDNF didn't reduce general anxiety or change the animals' tendency to move around. Further experiments showed that it also didn't completely 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, meaning they still froze when shocked.

"Many lines of evidence implicate BDNF in mental disorders," said Dr. Thomas Insel, director of NIH's National Institute of Mental Health (NIMH). "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."

The work was funded by NIMH, National Institute of Neurological Disorders and Stroke (NINDS), and National Center for Research Resources (NCRR).