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Female Bank voles as potential new animal models for Depression and General Anxiety Disorder (GAD)
Background for the study:
Following an idea from my former supervisor Knud Erik Heller, which initiated a cooperation with Frank Sams Dodd from Lundbeck A/S (Valby, Denmark), I designed and carried out a study in 1997 involving 56 stereotyping Bank voles. These were divided in three separate groups (equally matched gender wise and numerical), which received either a morning injection with Saltwater (Placebo; n= 19); Clozapine (n= 19; daily dose = 1.25 mg/kg) or Citalopram ("Cipramil"; n= 18; daily dose = 5 mg/kg). The injections lasted three weeks (19 injections in total/vole). 24-h video recordings were carried out six times: One week before the first injections; On the day for the first injection; after one weeks, two weeks and three weeks of injections and finally three weeks after last injection.
Our first publication (Schoenecker and Heller, 2001) concerned the results obtained from one hour of video surveillance in the time span of 25-26 hours after the injections and our second publication (Schoenecker and Heller, 2003) concerned the time span of 14-15 hours after the injections.
Serorotine and amount of stereotypies during handling.
The proportion of activity spend stereotyping was not influenced by Clozapine during the hour it took me to administer the daily dose to the voles which were to be video recorded that particular day. However, Citalopram significantly reduced the normally encountered rise in stereotypies due to disturbances such as handling. In Figure 1 (below) it can be seen that while 80-95% of the voles receiving Placebo or Clozapine engaged in stereotypic activity during the hour of injections, only around 40-60% of the Citalopram-trerated voles did so.
Figure 1 
Serorotine and amount of stereotypies during undisturbed conditions (Noon - low activity):
In the following video recordings (25-26 hours after injections) there were no effects of either treatment on the amount of stereotyping under such undisturbed conditions (Schoenecker and Heller, 2001). As discussed in the paper (and mentioned in Meers & Ödberg, 2006) a good explanation for this result could be that the half-life of Citalopram in Bank voles was too short to allow the treatment to exert a therapeutical effect after this long time. Another factor could very well be that we analyzed data from the lowest of the two peak-activities and it has earlier been observed that the amount of stereotypic activity follows the levels of general activity rather accurately with what seems to be a relative increase during peak activities (Ödberg, 1986).
Serorotine and amount of stereotypies during undisturbed conditions (midnight - high activity):
The focus of Schoenecker and Heller (2003) was to study how the treatments influenced the levels of stereotypies during the peak activity period in the hour before midnight and since these recordings took place 14-15 hours after the injections the concentration of Clozapin and Citalopram in the Bank voles would be higher than in our first study. The results of this study clearly demonstrated that treatment with Citalopram significantly reduced the amount of stereotypies among female Bank voles (Figure 2).
Figure 2
As seen in figure 2(a) there is no indication that the amount of normal activity was altered by the treatments. There were no significant inter- or intragroup differences, translating to no signs of sedation.
Figure 2(b) concerns amounts of stereotypies and the males (solid lines) showed no significant effect of treatments.
However, females (dotted lines) treated with Citalopram showed significant lower level of stereotypies than both females treated with Clozapine (p= 0.0246) and Placebo (p= 0.0337), which did not differ from each other (p= NS). This effect from Citalopram was significant after one week (p= 0.0257); two weeks (p= 0.0328); three weeks (p= 0.0194) and finally three weeks after last injection (p= 0.025). That neither males not females showed a significant drop in stereotypies the first day they received an injection is possibly related to the annoying fact that 1/3 of the 9 males/females in the group turned out not be have been monitored due to a malfunction of the video.
Apart from the initial increase in proportion of stereotypers immediately after the first injection, Placebo treated females showed a steady overall decrease in stereotypies in the course of this study (p= 0.049) suggesting a habituation towards the treatment procedure. This decrease was significant after one week (p= 0.028); two weeks (p= 0.0249); three weeks (p= 0.0298) and finally three weeks after last injection (p= 0.0251).
Other studies involving Bank voles and antidepressants:
Other studies involving Bank voles and antidepressants:
Apart from Schoenecker and Heller (2001; 2003) there has according to my best knowledge only been published one abstract and one paper.
Frank Olof Ödberg and Lieve Meers published an abstract in 1998, which is practically impossible to get today (Ödberg and Meers, 1998) concerning stereotyping Bank voles and treatment with Flouxetine, also known as Prozak. Flouxetine is an antidepressant in the same class as Citalopram; a so-called SSRI (Selective Serotonine Re-uptake Inhibitor). The abstract was later followed by a paper (Meers og Ödberg, 2005), and comments Schonecker, 2006, and it turned out that Bank voles reacted in two ways towards treatment with Fluoxetine. On one side there were a dosage effect; on the other there were an interesting interaction between individual levels of stereotypies before treatment, and the response towards the treatment. The method in this study was to take 24 stereotyping Bank voles and treat them with either 10- or 20 mg/kg/day while at the same time counting their daily jumps using an electronic counter. Unfortunately the sample sizes were too small to test for a gender-effect as in Figure 2 (above) (Meers and Ödberg, 2006).
The study showed that relatively low stereotyping Bank voles began to stereotype more as a result of the treatment whereas the initial high-stereotypers on the contrary reduced their number of average daily jumps. This so-called "Paradoxical rate-effect" was evident at both doses (10 and 20 mg/kg/day) and the greatest effect was seen using the highest dose of Fluoxetine.
Summing up:
Citalopram was originally perceived as an antidepressant, but has an anxiolytic effect too and is primarily used to treat mood- and anxiety disorders. The effect of treatment is rather individual: Some responds well, others hardly at all. Citalopram seems to have a certain effect on Obsessive Compulsive Disorders (OCD). Treatment with so-called "atypical" antidepressives as Citalopram (or Cipramil, as it is called too) is furthermore characterized with low levels of extra-pyrimidal sideeffects and not much sedation
Regarding animal studies, Ödberg and Meers (1998) showed that the effect of a rather similar treatment (Fluoxetine) depends by the initial level of stereotypies. Meers og Ödberg, 2005 showed in addition a dosage effect. Schoenecker and Heller, (2001) showed that Citalopram reduced the amount of stereotypies during handling and Schoenecker and Heller (2003) showed that female Bank voles reduced their stereotypies significantly during undisturbed conditions, whereas the males were not influenced. In the last paper I introduced the hypotheses that female bank voles could have potentials as new animal models for mood- and anxiety-related disorders.
These models are at present far from validated.
Last updated the 31th March, 2007