Scientists identify new pathway of antidepressant action

November 08, 1999

Scientists at UC San Francisco have discovered a new chemical pathway in the brain by which the most common antidepressants may alter mood. The research demonstrates that many popular mood modulators trigger chemical activity along more than one track at a time. It shows too how a brain chemical, known as a neurosteroid, might make a prime target for drugs to improve severe mood swings.

The researchers are publishing their study in the November 9 issue of the Proceedings of the National Academy of Sciences (PNAS).

Antidepressants such as Prozac, Paxil and Zoloft are thought to relieve depression by increasing the availability of one of the body's natural mood-enhancing chemicals, the neurotransmitter serotonin. But the UCSF experimenters examined the effect of these same antidepressants on an entirely different chemical pathway -- one increasingly thought to play a role in mood regulation as well. It involves a natural brain compound called a neurosteroid, only recognized in the last 10 or 15 years.

The scientists discovered that all three of these antidepressants, known as SSRI's, not only affect serotonin availability, but also greatly increase the synthesis of a key neurosteroid -- 10 to 30-fold. The profound effect, they found, comes from the SSRI's ability to greatly boost the action of the final enzyme involved in the synthesis of the neurosteroid in the brain.

"Each of these three serotonin reuptake inhibitors, or SSRI's, shows a dramatic positive effect on the levels of allopregnanolone, a steroid made in the brain, which most likely modulates mood and plays a role in heightened anxiety and depression found in severe premenstrual disorders and other conditions," said Synthia Mellon, PhD, senior author on the PNAS study and a professor of reproductive endocrinology at UCSF.

"The study points to the likelihood that SSRI's control mood by more than the one pathway that has received most of our attention, and it suggests that the steroids synthesized in the human brain may play a strong physiological role in regulating anxiety and depression."

Lead author on the PNAS paper is Lisa D. Griffin, MD, PhD, assistant professor of neurology at UCSF.

Studies by other researchers have shown below-normal brain neurosteroid levels among people with some depressive disorders, and SSRI's such as Prozac have been shown to elevate these brain steroid levels and alleviate symptoms of anxiety and depression among women suffering from a severe premenstrual disorder, Mellon and Griffin said.

Since the disorder occurs during a specific phase of the menstrual cycle, researchers have deduced that it is affected by levels of ovarian hormones such as progesterone. Subsequent studies, in rats, showed that Prozac does increase levels of the neurosteroid allopregnanolone, a derivative of progesterone, they said.

As a result of these and related studies, the brain's allopregnanolone has become a focus of interest in the continuing search for the body's natural mood modulators and what regulates them. The study reported by Mellon and Griffin clarifies the specific way SSRI's lead to increased neurosteroid levels. Interest in allopregnanolone has also been spurred by the fact that it is synthesized in the brain, unlike most of the body's potent steroids which are made in the sex glands. The term "neurosteroids" was coined to reflect the rather unexpected fact that the brain is the site of the steroid's synthesis.

While it is widely assumed that SSRI's relieve depression through their effect on the neurotransmitter serotonin, their effect on the neurosteroid allopregnanolone follows a different route: the so-called GABA pathway. In this pathway, the steroid boosts mood-enhancing neurotransmitter receptors by increasing how many and how long certain openings in the neuron's membranes --called GABA ion channels -- remain open. (The anti-anxiety medication valium works by stimulating this GABA pathway.)

To study the effects of the antidepressants on allopregnanolone, Griffin, Mellon and their laboratory colleagues cloned from both rat and human tissues the DNA (cDNA) of the intermediate enzymes known to be the key players in synthesizing the neurosteroid. They subjected both the rat and human enzymes to the antidepressants in solution. They tested the three SSRI's and a tricyclic antidepressant known as imipramine.

The scientists found that each of the three SSRI's greatly increased the affinity of both the rat and human enzyme 3-alpha HSD for the steroid precursor, resulting in surges of allopregnanolone synthesis. The tricyclic antidepressant showed no such effect.

Mellon says the research strengthens the likelihood that the enzymes that synthesize neurosteroids can make prime targets for mood-regulating drugs.

"We're interested in finding compounds that may directly affect these enzymes in the brain, and thus regulate mood disorders with minimal side effects," she said.

The research was supported by the National Institutes of Health and the National Alliance for Research on Schizophrenia and Depression.

University of California - San Francisco

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