Long-term citalopram treatment increases depressive-like behaviour and shows

no effect on hippocampal neurogenesis in a social stress model of depression.

J. Leach, M. Clarke, C. Rudyk, and S. Hayley
Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada

INTRODUCTION RESULTS
Major depression is the fourth-leading cause of
disability and premature death worldwide. Due to the
profound effects of depression upon the individual and it’s
more ubiquitous effect on global health and productivity,
the pursuit of pharmaceutical therapies for depression has
been a long-standing priority in mental health research.
A consistent feature of depression pathology is a
major reduction in serotonin availability in the brain. Thus,
the selective serotonin reuptake inhibitors (SSRIs), a
class of drug designed to enhance serotonin availability
by blocking its reuptake from the synapse, are among the
most prescribed pharmaceuticals worldwide. Among the
SSRIs, citalopram has demonstrated an ability to reverse
some neurological effects of depression .
Altered hippocampal neuroplasticity is a hallmark of
depression pathology. Because of the co-regulatory
relationship between serotonin and BDNF, it is believed
that serotonin reuptake inhibitors can play a key role in
Figure 1. Neither chronic social stress nor citalopram treatment Figure 2. Citalopram increases immobility in the forced-swim test while
enhancing cell survival and neuroplasticity in key brain
show an effect on neurogenesis in the dentate gyrus. stress shows no significant effect. Animals were scored on immobility
regions affected by depression including the
Doublecortin-positive cells were counted along the dentate gyrus over 6 minutes in 22±1oC water. Post-hoc analysis using Fisher’s
hippocampus.
of six evenly-spaced 40µm-thick coronal sections per animal PLSD shows no effect of stress (p < 0.08) and a main effect of
The present study utilizes a social stress model of taken from between -1.06mm and -2.46mm bregma. (n = 5 for citalopram (*p < 0.03). (n = 10 for both non-stressed groups and n = 9
depression since the social component of depression in each group except the stress/citalopram group for which n = 4) for both stressed groups)
humans is considerable. Herein, the effects of chronic
social stress and long-term citalopram treatment on
hippocampal neurogenesis will be analyzed.
CONCLUSIONS
 Citalopram treatment in this study
METHODS appears to have exacerbated behavioural
measures of depression. This may be a
Experimental Subjects product of serotonergic system behaving
Forty male CD1 mice (8-10 weeks) were singly housed differently in a social stress model.
and maintained on a 12 hour light/dark cycle with ad  Chronic social stress models are believed
libitum food and water. to induce social avoidance rather than
Experimental Design
Mice were randomly divided into four groups: (1) no stress
A B acting as a pure model of depression. As
such, a socially-oriented stress regimen
and vehicle; (2) chronic stress and vehicle; (3) no stress may preferentially affect areas more
and citalopram; (4) chronic stress and citalopram. related to social interaction (such as the
Citalopram-treated mice received 15mg/kg daily via their amygdala) rather than causing depression-
drinking water. like decreases in hippocampal volume.
Chronic Stress Regimen  If indeed social-avoidance is being
For 28 days, mice in the chronic stress condition endured preferentially conditioned, analysis of
alternating days with mild/unpredictable stress and highly glutamatergic activity in the amygdala may
stressful social encounters with one day off per week. The reveal why increased serotonin levels had
social stressor consisted of placing the experimental little effect on neurogenesis nor on open-
mouse in the home cage of a retired conspecific breeder field test performance (data not shown).
and allowing them to interact until they fought. Mice were Future studies will be directed towards
then separated by wire mesh but remained in the C D increasing sample size in order to more
breeder’s home cage for a total of 30 minutes. conclusively analyze the effects of the
Behaviour and Immunohistochemistry Figure 3. Doublecortin-positive neurons in the dentate gyrus (approximately -2.46mm bregma). All treatment on hippocampal neurogenesis,
The open field test and forced swim test were performed pictures taken at 10X magnification with Zeiss Axio Imager.M2 confocal microscope. (A) Non- assessing the long-term/lasting effects of
on Day 26 of the experiment. After sacrifice on Day 28, stressed, vehicle-treated mouse. (B) Stressed, vehicle-treated mouse. (C) Non-stressed, citalopram after treatment has ceased, and
coronal sections of hippocampal tissue were stained for citalopram-treated mouse. (D) Stressed, citalopram-treated mouse. analyzing other brain regions implicated in
doublecortin. depression.