Scientists at UC San Francisco have discovered a new chemical pathway in thebrain by which the most common antidepressants may alter mood. The researchdemonstrates that many popular mood modulators trigger chemical activity alongmore than one track at a time. It shows too how a brain chemical, known as aneurosteroid, might make a prime target for drugs to improve severe moodswings.
The researchers are publishing their study in the November 9 issue of theProceedings of the National Academy of Sciences (PNAS).
Antidepressants such as Prozac, Paxil and Zoloft are thought to relievedepression by increasing the availability of one of the body's naturalmood-enhancing chemicals, the neurotransmitter serotonin. But the UCSFexperimenters examined the effect of these same antidepressants on an entirelydifferent chemical pathway -- one increasingly thought to play a role in moodregulation 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 asSSRI's, not only affect serotonin availability, but also greatly increase thesynthesis of a key neurosteroid -- 10 to 30-fold. The profound effect, theyfound, comes from the SSRI's ability to greatly boost the action of the finalenzyme involved in the synthesis of the neurosteroid in the brain.
"Each of these three serotonin reuptake inhibitors, or SSRI's, shows adramatic positive effect on the levels of allopregnanolone, a steroid made inthe brain, which most likely modulates mood and plays a role in heightenedanxiety and depression found in severe premenstrual disorders and otherconditions," said Synthia Mellon, PhD, senior author on the PNAS study and aprofessor of reproductive endocrinology at UCSF.
"The study points to the likelihood that SSRI's control mood by more than theone pathway that has received most of our attention, and it suggests that thesteroids synthesized in the human brain may play a strong physiological role inregulating anxiety and depression."
Lead author on the PNAS paper is Lisa D. Griffin, MD, PhD, assistant professorof neurology at UCSF.
Studies by other researchers have shown below-normal brain neurosteroid levelsamong people with some depressive disorders, and SSRI's such as Prozac havebeen shown to elevate these brain steroid levels and alleviate symptoms ofanxiety and depression among women suffering from a severe premenstrualdisorder, 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 suchas progesterone. Subsequent studies, in rats, showed that Prozac does increaselevels of the neurosteroid allopregnanolone, a derivative of progesterone, theysaid.
As a result of these and related studies, the brain's allopregnanolone hasbecome a focus of interest in the continuing search for the body's natural moodmodulators and what regulates them. The study reported by Mellon and Griffinclarifies the specific way SSRI's lead to increased neurosteroid levels.
Interest in allopregnanolone has also been spurred by the fact that it issynthesized in the brain, unlike most of the body's potent steroids which aremade in the sex glands. The term "neurosteroids" was coined to reflect therather 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 effecton the neurotransmitter serotonin, their effect on the neurosteroidallopregnanolone follows a different route: the so-called GABA pathway. In thispathway, the steroid boosts mood-enhancing neurotransmitter receptors byincreasing how many and how long certain openings in the neuron's membranes--called GABA ion channels -- remain open. (The anti-anxiety medication valiumworks 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 tissuesthe DNA (cDNA) of the intermediate enzymes known to be the key players insynthesizing the neurosteroid.They subjected both the rat and human enzymes to the antidepressants insolution. They tested the three SSRI's and a tricyclic antidepressant known asimipramine.
The scientists found that each of the three SSRI's greatly increased theaffinity of both the rat and human enzyme 3-alpha HSD for the steroidprecursor, resulting in surges of allopregnanolone synthesis. The tricyclicantidepressant showed no such effect.
Mellon says the research strengthens the likelihood that the enzymes thatsynthesize neurosteroids can make prime targets for mood-regulating drugs.
"We're interested in finding compounds that may directly affect these enzymesin the brain, and thus regulate mood disorders with minimal side effects," shesaid.
The research was supported by the National Institutes of Health and theNational Alliance for Research on Schizophrenia and Depression.
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