The mania-like exploratory profile in genetic dopamine transporter mouse models is diminished in a familiar environment and reinstated by subthreshold psychostimulant administration

Abstract

Bipolar Disorder (BD) is a neuropsychiatric disorder characterized by symptoms ranging from a hyperactive manic state to depression, with periods of relative stability, known as euthymia, in between. Although prognosis for BD sufferers remains poor, treatment development has been restricted due to a paucity of validated animal models. Moreover, most models focus on the manic state of BD with little done to characterize the longitudinal behavior of these models. We recently presented two dopamine transporter (DAT) mouse models of BD mania: genetic (DAT knockdown; KD, mice) and pharmacological (the selective DAT inhibitor GBR 12909). These models exhibit an exploratory profile consistent with the quantified exploratory profile of manic BD patients observed in the cross-species translational test, the Behavioral Pattern Monitor (BPM). To further explore the suitability of these models, we examined the effects of reduced DAT function on the behavior of mice tested after familiarization to the BPM environment. Testing with 16mg/kg GBR 12909 in familiarized mice resulted in a consistent mania-like profile. In contrast, the mania-like profile of DAT KD mice disappears in a familiar environment, with partial reinstatement elicited by the introduction of novelty. In addition, we found that a subthreshold dose of GBR 12909 (9mg/kg) reinstated the mania-like profile in DAT KD mice without affecting wildtype behavior. Thus, the mania-like exploratory profile of DAT KD mice is reduced in a familiar environment, partially reinstated with novelty, but is fully restored when administered a stimulant that is ineffective in wildtype mice. These mice may provide a model of BD from mania to euthymia and back again with stimulant treatment. Acute blockade of the DAT by GBR 12909 however, may provide a consistent model for BD mania.

Figure 1. Schematic of the mouse Behavioral Pattern Monitor

The mouse BPM is an open activity chamber (30.5 × 61 cm) which records the spatial location of the mouse using a grid of 12 × 24 photobeams located 1 cm above the floor (A). The chamber contains eleven 1.4 cm diameter holes (3 in the floor, 3 on each long wall, 1 on each short wall), each provided with an infrared photobeam to detect investigatory holepokes (B). The chamber is divided into 9 unequal regions (B), with transitions between regions utilized as a measure of investigatory activity.

Figure 2. Activity levels of DAT KD and WT mice on repeated testing

Previous reports indicate a mania-like phenotype in BPM-naïve DAT KD mice. The present data reassessed the consistency of this phenotype by retesting the same animals in the BPM. The mania-like phenotype was almost entirely absent upon repeated testing, with an increase in transitions observed only during the first 10 min (A). In contrast to behavior when BPM naïve, DAT KD mice did not exhibit an increase in holepoking (B). No difference in rearing was observed, consistent with previous reports, but in contrast, no change in spatial d was evident (D). Data collapsed across sex and presented as mean ± s.e.m., * denotes p < 0.05 when compared to vehicle control.

Figure 3. Exploratory behavior of DAT WT and KD mice in a modified BPM environment

The same DAT WT and KD mice were reassessed in the BPM but with a modified environment in half of the BPM chambers. The BPM was altered by placing sandpaper on the floor, as well as inserting novel objects in four of the holes in the chambers. This novel environment was created to ascertain whether it would reinstate the mania-like phenotype of DAT KD mice observed when first placed in the BPM. The novel environment did elicit a significant increase in transitions in DAT KD, but not WT mice (A). Although the novel environment increased holepoking in DAT KD mice consistent with the increase in transitions, this effect was not significant (B). No effect of environment on holepoking was observed in WT mice either (B). Environment had no effect on rearing (C) in DAT KD or WT mice, with varying effects on spatial d in these mice (D). Data collapsed across sex and presented as mean ± s.e.m., * denotes p < 0.05 when compared to WT control mice, # denotes 0.05 when compared to KD mice in the normal (control) environment.

Figure 4. Effects of GBR 12909 on exploratory behavior in BPM non-naïve C57BL/6J mice

Mice that had previously exposed to the BPM were administered various doses of the selective DAT inhibitor GBR 12909 prior to their assessment in the mouse BPM. The doses used in the present study induced a consistent effect on exploratory behavior to that of the previous study. Both 16 and 28 mg/kg GBR 12909 increased transitions, with doses 10 and 13 mg/kg exhibiting a modest increase in transitions, while 9 mg/kg did not affect activity in mice (A). Again, consistent with previous reports, 16 mg/kg induced a modest increase in holepokes while 28 mg/kg reduced holepoking (B). GBR 12909 at 16 mg/kg also consistently increased rearing (C). Numerous doses of GBR 12909 including 10, 13, and 16 mg/kg, significantly reduced spatial d (D). Data presented as mean ± s.e.m. where * denotes p < 0.05 when compared to vehicle administered control mice.

Figure 5. Sensitivity of DAT KD mice to a sub-threshold dose of GBR 12909

DAT WT and KD mice were reassessed in the BPM, with half administered 9 mg/kg GBR 12909, a dose determined to be ineffective to altering exploratory behavior in C57BL/6J mice. GBR 12909 significantly increased transitions (A), holepoking (B), and rearing (C) in DAT KD mice but not WT mice. DAT KD mice also exhibited reduced spatial d when administered GBR 12909, again in contrast with WT mice (D). Thus DAT KD mice exhibited a sensitivity to GBR 12909 at a dose that was ineffective in altering behavior in WT mice. Data collapsed across sex and presented as mean ± s.e.m. where * denotes p < 0.05 when compared to WT control mice at the same dose. # denotes p < 0.05 compared to KD mice administered vehicle.

Figure 6. Summary of repeated testing of DAT KD mice in the mBPM

DAT KD mice in a normal mBPM environment (○) initially exhibited hyperactivity compared to WT mice (●) (Perry et al., 2009) that disappeared by the second stage of testing (experiment 1). The introduction of novelty stimulated activity in the DAT KD mice (△) but not WT mice (▼) in the third stage of testing (experiment 2), while a sub-threshold dose of GBR 12909 vastly increases activity in DAT KD mice (△) compared to WT mice (▼), and KD mice administered vehicle (○) (experiment 3). Data collapsed across sex and presented as mean.