Fear-Reducing Drugs – An Emerging Science?

A new animal study reveals that a brain protein can reduce the expression of fear when infused into specific parts of the brain involved in behavioral responses to fear-inducing stimuli. The findings have important implications for the possible development of new drug therapies that can mimic these effects in humans with anxiety disorders or post-traumatic stress disorder.

Brain-derived neurotrophic factor (BDNF) is a brain protein that has been implicated in the expression of fearful behaviors in both humans and animals. A number of studies have shown that BDNF and related proteins play an important role in psychiatric conditions such as anxiety and depression. The role of BDNF in behavioral fear responses is currently a subject of intense investigation.

A research team headed by Dr. Gregory Quirk at the University of Puerto Rico School of Medicine thought that it might be possible to reduce the expression of fear in rats by manipulating levels of BDNF in specific parts of the brain thought to be involved in the expression of fearful behaviors.

To investigate, the research team trained rats to become fearful of a tone that was paired to a mild footshock in a procedure known as auditory fear conditioning. In order to test how fearful the rats had become of the tone, the researchers tested how much time the rats spent engaged in freezing behavior, in which rats cease physical movements and appear frozen for a brief period around the time of a fear-inducing event (in this case, the tone). On subsequent tests, the rats were trained to become less fearful of the tone by no longer pairing it to a footshock. After this so-called extinction training, freezing behavior could again be observed in order to determine the degree to which the rats no longer feared the tone.

In a study published in Science, the researchers demonstrated that, after auditory fear conditioning, fearful rats show better performance in response to extinction training (i.e., show reduced fear of the tone, as shown by reduced freezing behavior) when BDNF is infused into a part of the brain called the infralimbic pre-frontal cortex, a structure involved in behavioral expressions of fear. Remarkably, even when BDNF was given in the absence of extinction training, the rats showed reduced freezing behavior. Importantly, BDNF had no effect on the initial learning of fear, but only affected its behavioral expression.

In additional experiments, the researchers show that rats exhibiting better extinction of fear had increased levels of BNDF (than more fearful rats) in the hippocampus, a brain structure that activates the infralimbic pre-frontal cortex. Furthermore, in rats treated with drugs to inactivate the effects of BDNF in the infralimbic pre-frontal cortex, BDNF infusions no longer resulted in enhanced extinction (i.e., reduced fear behavior).

Together, the findings shed light on the workings of brain circuits responsible for behavioral expressions of fear, as well as suggest how they can be manipulated with drugs to reduce fearful behaviors. The researchers suggest that these results may help pave the way for future efforts to treat humans with anxiety disorders or post-traumatic stress disorder. This study is particularly timely because, earlier this year, other studies reported that a single change in the DNA sequence in the gene responsible for producing BDNF is associated with impaired fear extinction and increased anxiety in humans.

BDNF and related proteins have been extensively studied in humans and animals, but drugs intended to manipulate levels of BDNF in human brains have not yet been developed. The remaining challenge is to apply findings from animal studies of BDNF to drug discovery and clinical settings, where drugs can be developed and tested, respectively, for their ability to increase BDNF levels in brain circuits mediating fear behaviors in humans. Since BDNF can substitute for extinction training (i.e., training to no longer be fearful) in animals, its future applicability to pharmacotherapeutics in humans with anxiety disorders or post-traumatic stress disorder is a viable possibility.

References

Alleva E, & Francia N (2009). Psychiatric vulnerability: suggestions from animal models and role of neurotrophins. Neuroscience and biobehavioral reviews, 33 (4), 525-36 PMID: 18824030

Montag C, Basten U, Stelzel C, Fiebach CJ, & Reuter M (2010). The BDNF Val66Met polymorphism and anxiety: Support for animal knock-in studies from a genetic association study in humans. Psychiatry research, 179 (1), 86-90 PMID: 20478625

Peters J, Dieppa-Perea LM, Melendez LM, & Quirk GJ (2010). Induction of fear extinction with hippocampal-infralimbic BDNF. Science (New York, N.Y.), 328 (5983), 1288-90 PMID: 20522777

Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, Jing D, Tottenham N, Amso D, Somerville LH, Voss HU, Glover G, Ballon DJ, Liston C, Teslovich T, Van Kempen T, Lee FS, & Casey BJ (2010). A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science (New York, N.Y.), 327 (5967), 863-6 PMID: 20075215