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
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
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
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....>.▪