Startling Rat Findings Could Lead To Novel Antianxiety Drugs

For some time, the case has been building that a brain peptide called corticotropin-releasing factor (CRF) plays a role in anxiety. For example, elevated levels of CRF have been found in the brains of people with some types of anxiety. Also, if rats are injected with CRF, it can make them startle excessively when they are exposed to noise—a reaction believed to reflect anxiety.

Moreover, there have been reasons to believe that the neurotransmitter dopamine might interact with CRF to trigger anxiety in the brain. For example, levels of dopamine, like those of CRF, are increased in the brain after stress.

Edward Meloni, Ph.D., an instructor in psychiatry at Harvard University and McLean Hospital, and coworkers decided to conduct an animal study to learn more about dopamine's possible complicity in CRF-enhanced startling.

When rats were treated with a dopamine D₁ receptor antagonist, the researchers found, the animals showed a significant dose-dependent reduction in the startle-exaggerating effects of injected CRF.

This result suggested that dopamine was complicit with CRF in enhancing startle responses. Furthermore, the doses of the dopamine antagonist that reduced the CRF-exaggerated startling did not affect the animals' normal startle responses (that is, those that were not CRF enhanced). This finding implied that dopamine was involved in producing the CRF-enhanced startle responses, but not the normal startle responses.

The scientists then examined the rats' brains to determine how dopamine might work with CRF to provoke an excessive startle reaction. They found that an area of the brain known to be rich in CRF neurons—the bed nucleus of the stria terminalis (BST)—also showed a lot of innervation from dopamine-producing neurons.

Thus, dopamine may not only interact with CRF to trigger an excessive startle reaction, but also does so in the BST, Meloni and his group concluded in their report in the April 5 Journal of Neuroscience.

Meloni and his colleagues also believe that dopamine may interact with CRF in the BST of humans to provoke anxiety states. After all, as Meloni told Psychiatric News, one study showed a dense dopaminergic innervation in the BST of humans that almost precisely mirrors what he and his team found in the BST of rats.

But the most intriguing implication of their findings, the researchers said in their report, is that dopamine D₁ receptor antagonists might constitute new types of anxiety drugs for humans. In fact, one of Meloni's colleagues in the study—Bruce Cohen, M.D., a professor of psychiatry at Harvard—is now attempting to launch a clinical trial to see whether a D₁ antagonist might help people with posttraumatic stress disorder (PTSD) or panic disorder.

He and his colleagues decided to focus on PTSD and panic disorder rather than on other anxiety disorders, Cohen explained, because CRF-enhanced startle responses seem to resemble the abnormal startle reactions displayed by patients with those illnesses, especially PTSD.

“But as anyone who works with these patients knows,” Cohen added, “they are not all alike.... [For example] cortisol levels can go very high in some subsets of PTSD patients and in some subsets of panic-disorder patients. And it may be exactly those people who would be helped most by a dopamine D₁ receptor antagonist.”

And assuming that a dopamine D₁ receptor antagonist is eventually found to help certain PTSD and panic patients, and that it is ultimately approved by the Food and Drug Administration for treating such patients, it would constitute the first dopamine D₁ receptor antagonist on the market, Meloni said. True, he admitted, there are already medications on the market that act on dopamine—for instance, the antipsychotic clozapine has a relatively balanced affinity for dopamine D₁ receptors and dopamine D₂ receptors (Psychiatric News, September 17, 2004). But this would be the first pure D₁ antagonist, he stressed.

The study was funded by the Stanley Medical Research Institute and the National Institute of Mental Health.

An abstract of “Behavioral and Anatomical Interactions Between Dopamine and Corticotropin-Releasing Factor in the Rat” is posted at<www.jneurosci.org/cgi/content/abstract/26/14/3855?maxtoshow=&HITS=10&hits=10....>.▪