Posted by jrbecker on April 11, 2005, at 8:45:00
http://www.healthday.com/view.cfm?id=524979
Newer Antidepressants Work 2 Ways
SSRIs boost serotonin levels on two fronts, study showsBy Amanda Gardner
HealthDay Reporter
WEDNESDAY, April 6 (HealthDay News) -- New research shows that the popular, and sometimes controversial, antidepressants known as selective serotonin reuptake inhibitors (SSRIs) boost serotonin levels on two fronts.The finding could explain why these medications often take weeks to work, the scientists report in the April 7 issue of Neuron. Apparently, SSRIs kick off a two-pronged process that puts serotonin levels back into balance. Serotonin is a brain chemical that scientists believe is in short supply in depressed people.
In addition to boosting serotonin levels, this family of antidepressants apparently also "hijacks" the dopamine signaling system, causing it to affect serotonin levels as well.
The use of SSRIs, especially by children, came into question last fall following reports of increased thoughts of suicide and attempts among young, depressed patients. The U.S. Food and Drug Administration responded by mandating a black box warning on the use of these drugs in children and teenagers.
"We have known about these interrelationships," said Dr. Fred Quitkin, director of the depression evaluation service at the New York State Psychiatric Institute. "It's of interest, but no one knows what it means."
"The brain is so incredibly complicated," said Dr. Eugenio M. Rothe, director of the child and adolescent psychiatry clinic at Jackson Memorial Hospital in Miami, Fla., and an associate professor of psychiatry at the University of Miami School of Medicine. "More and more things have yet to be discovered. The brain is the final frontier."
Many of the millions of Americans afflicted with depression have a disorder in the brain's reward system, explained study author Fu-Ming Zhou, an assistant professor of pharmacology at the University of Tennessee College of Medicine in Memphis. Zhou conducted the study while at the Baylor College of Medicine.
"A large body of research indicates that the dopamine system is the most important player in the reward system," he added.
Often, however, depression is treated with medications that affect the serotonin system. SSRIs block the reuptake of serotonin back into the nerve terminals.
In a healthy person, serotonin is stored in nerve terminals and then released into the spaces between neurons. Problems occur when the neurotransmitter is sucked back into the terminal, a process called reuptake. "This limits the level or availability of serotonin near the nerve terminals," Zhou said. "There is a possibility, which remains to be proven, that the local serotonin level near these nerve terminals is abnormally low in depressed patients."
"When a patient takes an SSRI, the reuptake process is inhibited, leading to increased serotonin levels around the nerve terminal, and also restored or enhanced serotonin signaling," he continued. "This restored or enhanced signaling is often believed to be the major therapeutic mechanism of SSRIs."
Apparently, however, SSRIs affect more than just serotonin levels, as Zhou and his colleagues demonstrated in mice.
Dopamine transporters in the brain area involved in reward response normally reuptake dopamine. But because there are so many dopamine transporters, they may also pick up serotonin, albeit at a lower level of efficiency.
"Put simply: serotonin transporters are like a high-power vacuum pump that can suck back serotonin really fast," Zhou said. "Dopamine transporters may suck back serotonin very slowly, like a large sponge. This sponge is of no significance if the high power vacuum pump is working. When a patient takes SSRI, the pump is inhibited or becomes not functional. Under this condition, the large sponge becomes significant, capable of sucking in significant amounts of serotonin over a long period of time."
"We believe that these neurochemical changes contribute to the therapeutic mechanisms of SSRIs," Zhou said.
The fact that the "sponge" is not very efficient may account for why it can take several weeks for the effects of Prozac and other SSRIs to kick in, he added.
The authors also speculated that disrupting normal serotonin levels in children, while neurons are still under development, could result in problems later in life.
Although the study was done in mice, Rothe believes there is a message for humans.
"People taking antidepressants need to have regular doctor visits, and their doctor has to keep a close eye on what's going on," he said. "They should fight insurance companies that think that they can go for one visit and get five refills, and not go back for six months.
_____________from the journal Neuron...
Neuron
Volume 46, Issue 1 , 7 April 2005, Pages 1-2
doi:10.1016/j.neuron.2005.03.013
PreviewAntidepressants and the Monoamine Masquerade
David Sulzer1, , and Robert H. Edwards2
1Departments of Neurology, Psychiatry, and Pharmacology, Columbia University, Department of Neuroscience, New York State Psychiatric Institute, New York, New York 10032
2Departments of Neurology and Physiology, University of California, San Francisco, School of Medicine, San Francisco, California 94143Available online 7 April 2005.
Neurotransmitter transporters have long been known to recognize related compounds as substrates, resulting in the accumulation and release of so-called “false transmitters.” In this issue of Neuron, Zhou et al. show that when serotonin levels are elevated by inhibition of either serotonin reuptake or of monoamine oxidase, dopamine neurons accumulate serotonin. The results suggest that release of serotonin by dopamine neurons may contribute to the effects of multiple major classes of antidepressants.
Article Outline
Main Text
References
Main Text
Plasma membrane uptake systems have long been known to accumulate different neurotransmitters somewhat promiscuously. Indeed, the initial discovery of plasma membrane transmitter uptake, in 1958 by Barbara Hughes, a fellow in Bernard Brodie’s laboratory at the National Heart Institute (Hughes and Brodie, 1959 and Hughes et al., 1958), included evidence that the monoamine transmitters (serotonin and the catecholamines) are recognized as substrates by the same reuptake system.Hughes and Brodie examined the uptake of serotonin, epinephrine, and norepinephrine in guinea pig platelets. The uptake of serotonin was more rapid than for the catecholamines, but all were substrates for the same system, as indicated by inhibition of accumulation by reserpine, a plant extract used to treat mental illness in India that was eventually found to inhibit specifically the uptake of monoamines into secretory vesicles. Although we now know that reserpine does not inhibit plasma membrane uptake, Hughes correctly concluded that there was “an endergonic mechanism that rapidly extracts serotonin from the surrounding medium against a concentration gradient.”
An independent line of early investigation led to the so-called “false transmitter hypothesis,” which suggested that different monoamines could be packaged into the same synaptic vesicle. Once plasma membrane transporters have accumulated monoamines into the cytosol, the transmitters are either taken up into synaptic vesicles or metabolized by monoamine oxidase (MAO). The first widely prescribed class of antidepressants were MAO inhibitors, which, as might be predicted, enhanced serotonin and catecholamine levels. Clinicians noted, however, that MAO inhibitors sometimes caused hypertension in patients who had consumed red wine, beer, and cheese. Irwin Kopin (Kopin, 1968) suggested that nonneurotransmitter monoamines such as tyramine, a decarboxylated tyrosine metabolite that is normally metabolized by MAO, could act as false transmitters that would be accumulated into vesicles and then released. Tyramine, which can be produced at high levels by yeast and microbes during the manufacture of these foods, and its metabolite octopamine indeed turned out to be the culprits responsible for hypertension in cheese-eating patients (Blackwell and Mabbitt, 1965).
A molecular basis of false transmitter action became clear after the identification and cloning of most of the plasma membrane and vesicular neurotransmitter transporters in the early 1990s. The dopamine uptake transporter (DAT) is exclusively expressed in neurons that synthesize and release dopamine, the norepinephrine transporter (NET) by noradrenergic neurons, and the serotonin transporter (SERT) by serotonergic neurons, and the proximity of release and reuptake sites presumably helps to load the correct transmitter into each neuron’s synaptic vesicles. Consistent with Barbara Hughes’ early report, however, each monoamine transporter accumulates the monoamines made by other cells. For example, NET has a higher apparent affinity for dopamine than norepinephrine (Gu et al., 1994). Mice lacking DAT still self-administer cocaine (Rocha et al., 1998), suggesting that NET or SERT can contribute to dopamine’s clearance.
In contrast to the selective distribution of the plasma membrane transporters, the vesicular monoamine transporter 2 (VMAT2) is expressed by all monoamine neurons. Both VMAT2 and VMAT1 (expressed in nonneural cells) accumulate serotonin and catecholamines, as well as classic false transmitters such as tyramine. Moreover, they recognize serotonin with at least a 3-fold higher apparent affinity than dopamine, but transport serotonin more slowly (Peter et al., 1994). Although the significance of these differences in substrate recognition has remained unclear, they are conserved across species (Erickson and Eiden, 1993) and raise the possibility that serotonin might be able both to accumulate in the synaptic vesicles of dopamine neurons and to inhibit the packaging of dopamine. There are several reports of serotonin acting as a false transmitter in dopamine terminals following pharmacological interventions, as well as evidence suggesting that serotonin may normally act as a false transmitter at dopamine terminals in the intermediate lobe of the pituitary (Vanhatalo and Soinila, 1995).
Although the plasma membrane monoamine transporters show some promiscuity in substrate recognition, the clinical efficacy of many antidepressants indicates that the transporters each have distinct roles. The “tricyclic” desipramine (Norpramin) is particularly selective for NE, and paroxetine (Paxil) and fluoxetine (Prozac) are particularly selective for SERT. Interestingly, selective DAT inhibitors have not emerged as effective antidepressants, raising the possibility that MAO inhibitors and serotonin-selective reuptake inhibitors (SSRIs) result in the accumulation of serotonin as a false transmitter by dopamine neurons. Consistent with this possibility, serotonin accumulation by dopamine neurons was observed in mice lacking the SERT gene and wild-type animals treated with paroxetine (Zhou et al., 2002). Serotonin uptake by catecholamine neurons was also observed in mice lacking one of the monoamine oxidase genes (MAO-A) (Cases et al., 1998).
The evidence that antidepressants induce serotonin accumulation by dopamine neurons has now been significantly advanced by a study in this issue of Neuron from John Dani’s laboratory (Zhou et al., 2005). The investigators adapted rapid electrochemical measurements of evoked dopamine and serotonin release in acute “horizontal” slices that encompass a portion of the innervating axons from midbrain dopamine neurons, and their primary target area, the striatum, where both dopamine and DAT are present at far higher levels than serotonin and SERT. To record dopamine and serotonin release evoked by electrical stimuli, they used cyclic voltammetry, in which ramp voltages are applied to a carbon fiber electrode and that to some extent differentiates the transmitters on the basis of the I-V relationships of their oxidation and reduction peaks. They further noted that the serotonin component could be identified, due to the relatively greater adsorption of serotonin to the carbon surface, simply by analyzing a later point during the signal’s falling phase.
When the investigators exposed striatal tissue to fluoxetine in the presence of nisoxetine, a specific NET inhibitor, evoked serotonin release increased, whereas dopamine release decreased. Serotonin may thus act as a false transmitter after exposure to SSRIs. The signal, however, represents the release of transmitter from hundreds of synaptic vesicle fusion events and could alternatively reflect an enhanced release of serotonin from its native terminals. They addressed this possibility by examining nonevoked spontaneous release events, which are much smaller and likely reflect transmitter release from dozens of synaptic vesicles at synaptic varicosities along the incoming dopamine fibers. Each of these smaller events likewise contained both dopamine and serotonin, further evidence consistent with corelease. Perhaps more convincingly, fluoxetine’s effect was inhibited by the selective DAT inhibitor GBR12909, as would be predicted if the serotonin was accumulated by DAT. The authors thus conclude that when SERT is blocked by SSRIs, serotonin acts as a false transmitter in dopamine neurons. Experiments in vivo suggest that the effect may require several days of administration, which could underlie the well-known delay in full therapeutic benefit of these drugs. And to bring the story full circle, they found that the MAO inhibitor clorgyline further promotes serotonin uptake and release by dopamine neurons.
The data clearly indicate that, at least under some conditions, both major classes of antidepressants cause serotonin to act as false transmitter in dopamine neurons. It is not yet known if such serotonin release by dopamine neurons contributes to the therapeutic effect of these agents, and it would be very interesting to know whether inhibition of DAT blocks the antidepressant effects of SSRIs. The Dani lab, in the meantime, can take credit for an elegant proof of a phenomenon that may underlie the effects, and perhaps the delayed response, for the many patients who take these drugs. And well in time for the 50th anniversary of Hughes’ and Brodie’s seminal discovery.
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