1) IntroductionSelective 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.

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 administered over 4 weeks.

-Control mice were given just water with or without saccharin.

-Behavioral tests began after 4 weeks of treatment. -Open Field Test -Forced Swim Test -Tail Suspension Test

-Anesthetized mice were decapitated and both hippocampi were isolated. Hippocampi were sliced into thin sheets and electrophysiology recordings were taken.

4) Results-EPSP in FLX22 animals had significantly reduced granule cell firing rate as indicated by electrophysiology recordings in figure 5.

-Granule cell dematuration as indicated by figure 5 is associated with increased anxiety related behavior displayed in figure 6

5) Conclusions/Discussion-This present study has shown that chronic administration of fluoxetine can lead to erratic changes in home cage behavior. -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.

Behavioral destabilization induced by the selective serotonin reuptake inhibitor fluoxetineKatsunori Kobayashi, Yumiko Ikeda, Hidenori Suzuki—Department of Pharmacology, Nippon Medical School, Tokyo, Japan

6) Literature cited1Kobayashi et al.: Behavioral destabilization induced by the selective serotonin reuptake inhibitor fluoxetine.

Molecular Brain 2011 4:12.2Ali S, Milev R: Switch to mania upon discontinuation of antidepressants in patients with mood disorders: a review

of the literature. Can JPsychiatry 2003, 48:258-264.3Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O,

Belzung C, Hen R: Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants:Science 2003, 301:805-809.

Fig. 2 (Left). Open field test was used to measure home cage activity. It was performed using an infrared camera mounted at the top of mouse cage. It measured horizontal activity and fed data into a personal computer.

Fig. 3(Right). Illustration of forced swim test apparatus. Mice are placed into clear plastic cylinders filled with 25° C water, and are forced to swim for 15 minutes.

Figure 1

Fig. 1. Typical 8 week-old adult mouse used for the study.

Fig. 4 (Left). Image of tail suspension test in progress. Tail suspension is used to evaluate depression related symptoms

Fig. 5. (Above) Data collected from control (CNT), 14mg/kg/day (FLX14) , and 22mg/kg/day (FLX22). The CNT and FLX14 groups returned similar data, however, FLX22 cage behavior was shown to be erratic.

Fig. 6. (Right) FLX14 and FLX22 is associated significantly less time spent immobile during the tail suspension test. However FLX 14 and FLX22 is associated with higher time spent immobile during forced swim test.

Rodion Stolyar rodionst@umich.edu