1. Behavioral destabilization induced by the
selective serotonin reuptake inhibitor fluoxetine
Katsunori Kobayashi, Yumiko Ikeda, Hidenori Suzuki—Department of Pharmacology, Nippon Medical School, Tokyo, Japan
1) Introduction
Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to
patients with mood and anxiety disorders1. However, the neural mechanism by
which these drugs work is poorly understood. Previous studies have shown
chronic administration of fluoxetine, a commonly prescribed SSRI, can
reverse the state of maturation of hippocampal granule cells in adult mice2.
These “dematuration” effects are characterized by functional and
physiological changes seen in a large number of the hippocampal granule cells.
In this study, we are able to show this type of neural plasticity is associated
with a marked change in mice behavior3.
Fig. 1. Typical 8 week-old adult mouse used for
the study.
2) Materials and methods
-Adult male mice were singly housed in climate controlled rooms with a set
light/dark cycle: lights on at 6:00AM through 8:00PM.
-Fluoxetine solutions were prepared daily, administer at either 14 or
22mg/kg/day, dissolved in drinking water, and sweetened with saccharine and Figure 1
administered over 4 weeks.
-Control mice were given just water with or without saccharin. Fig. 5. (Above) Data Fig. 6. (Right) FLX14 and
collected from control FLX22 is associated
-Behavioral tests began after 4 weeks of treatment. (CNT), 14mg/kg/day significantly less time
-Open Field Test (FLX14) , and spent immobile during
-Forced Swim Test 22mg/kg/day (FLX22). the tail suspension test.
-Tail Suspension Test The CNT and FLX14 However FLX 14 and
groups returned similar FLX22 is associated with
-Anesthetized mice were decapitated and both hippocampi were isolated. data, however, FLX22 higher time spent
Hippocampi were sliced into thin sheets and electrophysiology recordings were cage behavior was immobile during forced
taken. shown to be erratic. swim test.
Fig. 2 (Left). Open field test was
used to measure home cage
4) Results
activity. It was performed using -EPSP in FLX22 animals had significantly
an infrared camera mounted at reduced granule cell firing rate as indicated
the top of mouse cage. It by electrophysiology recordings in figure 5.
measured horizontal activity
and fed data into a personal
-Granule cell dematuration as indicated by
computer.
figure 5 is associated with increased anxiety
related behavior displayed in figure 6
Fig. 3(Right). Illustration of forced 5) Conclusions/Discussion
swim test apparatus. Mice are -This present study has shown that chronic administration of fluoxetine can lead to
placed into clear plastic cylinders erratic changes in home cage behavior.
filled with 25° C water, and are
forced to swim for 15 minutes. -This change in behavior has been shown to be associate with the dematuration of
hippocampal granule cells caused by chronic treatment with fluoxetine.
-The hippocampus plays a critical role regulating activity levels in familiar
environments.
-Destabilization of mouse behavior occurred at a higher than therapeutic dose,
therefore the effects observed may not be relevant to human SSRI treatment.
Fig. 4 (Left). Image of tail
6) Literature cited
1Kobayashi et al.: Behavioral destabilization induced by the selective serotonin reuptake inhibitor fluoxetine.
suspension test in progress. Molecular Brain 2011 4:12.
2Ali S, Milev R: Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review
Tail suspension is used to
of the literature. Can JPsychiatry 2003, 48:258-264.
evaluate depression related 3Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O,
symptoms Belzung C, Hen R: Requirement of hippocampal neurogenesis for the behavioral effects of
antidepressants:Science 2003, 301:805-809.
Rodion Stolyar rodionst@umich.edu