Prozac Linked to Long Term Behavioral Problems In Mice Study

A recent study in Japan tested the chronic use of fluoxetine (commonly known as Prozac) on the cellular level. Fluoxetine is a widely used medication against depression. It falls in the group of selective serotonin reuptake inhibitors (SSRIs). The test was conducted to analyze behavioral changes in adult male mice while on this medication. As a result of taking this medication, there was an increase in anxiety-related behavior in the mice, which remained even after four weeks of withdrawal of the drug. It was observed that fluoxetine treatment reversed the maturation of specialized brain cells and that this was responsible for the behavioral changes observed in the mice.

Fluoxetine is commonly used as a mood-enhancing drug. It works immediately by changing the serotonin levels, which in turn impacts signals from the nerve to the target cells. An adverse psychiatric effect is seen after chronic use of this medicine and even after withdrawal of the treatment. It is necessary to understand the cellular mechanism behind these effects, for a better understanding of the antidepressant mechanism of this medication. A chronic test of fluoxetine on mice showed that prolonged use of the drug reversed the maturation of specialized brain cells. It inhibited the aging process in the nerve cells, causing a reversal of the juvenile state and did not enable the cells to function properly. This led to mood switching and behavioral changes in the test animals.

* Singly housed normal male mice and suitable mutants lacking serotonin receptors were treated orally with fluoxetine for four weeks and then further examined.
* A withdrawal time of four weeks was provided before behavioral tests were conducted; medication was continued during behavioral tests.
* Home cage activity was continuously monitored using infrared video camera and the images taken were then analyzed.
* Several behavioural tests like open-field test, light/dark transition test and electrophysiology tests were conducted to understand the cellular makeup of nerve cells on medication.

* Chronic fluoxetine treatment, at 22mg/kg/day, showed destabilization of home cage activity in the mice, which was caused by the changes induced in the central nervous system.
* Increase in anxiety-related behavior was observed as a result of chronic medication.
* Age-reversal phenomenon was observed in specialized brain cells, leading to the anxiety related behavior.
* Behavioral destabilization was not observed in mutated mice lacking the serotonin receptor.

Next steps/Shortcomings
The study was done on a mouse model; further related studies should be done on a human model. There are several anti-depressant drugs in the market, which might have similar adverse effects or prolonged effects on withdrawal. A systematic comparative study can lead to proper understanding of the cellular mechanism involved in the functioning of these drugs.

Fluoxetine is a common drug for the treatment of depression. The preliminary explanation for the efficacy of this drug was that it increases the level of serotonin, which is a feel-good hormone. But in prolonged use, mood swings or behavioral destabilization were observed as a side effect. This study was aimed at understanding the cellular basis of the mood-switching behavior observed upon prolonged use of this antidepressant. Critical observation of normal and mutant mice models has shown that prolonged use of fluoxetine induces reversal of the maturation of specialized brain cells in mice. This brings about a juvenile state in the nerve cells, leading to switching of activity and anxiety levels.

For More Information:
Behavioral Destabilization Induced by the Selective Serotonin Reuptake Inhibitor Fluoxetine
Publication Journal: Molecular Brain, March 2011
By Katsunori Kobayashi; Yumiko Ikeda; Nippon Medical School, Tokyo, Japan and Core Research for Evolutional Science and Technology, Saitama, Japan

*FYI Living Lab Reports Are Summaries of the Original Research.


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