GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Abstract

Rationale: Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d.

Objectives: It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM.

Methods: We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice.

Results: Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h.

Conclusions: Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania.

Fig. 1

Effects of amphetamine on exploratory behavior in C57BL/6J mice in the mouse BPM. The nonselective NET and DAT inhibitor amphetamine was administered to mice at various doses prior to their exploration in the mouse BPM. Exploratory behavior was measured as activity levels—transitions (a), specific exploration—holepokes (b) and rearing (c), as well as locomotor pattern—spatial d (d). An inverted U-shaped dose–response was observed for amphetamine effects on activity where a low dose (2.5 mg/kg) increased activity levels while higher dose (10 mg/kg) lowered activity levels (a). The only effect of amphetamine on specific exploration, however, was to reduce holepoking at all but the lowest dose (b), with no effect on rearing (c). Consistent with activity levels, there was a separation of effects between a low (2.5 mg/kg) and high (10 mg/kg) dose, with some reduction in spatial d at low and increased spatial d at high doses (d). Data presented as mean ± SEM. *p < 0.05 when compared to vehicle control

Fig. 2

Effects of GBR 12909 on exploratory behavior in C57BL/6J mice in the mouse BPM. Mice were administered various doses of the selective DAT inhibitor GBR 12909 prior to the assessment of their exploration in the mouse BPM. Exploration was measured in the BPM for activity levels—transitions (a), exploration—holepoking (b) and rearing (c), as well as locomotor patterns—spatial d (d). GBR 12909 increased activity at the highest (16 and 28.5 mg/kg) doses tested (a). The effects of GBR 12909 on exploration differed by dose and measure—the highest dose lowered holepoking (b) while the second highest dose increased rearing (c). Data presented as mean ± SEM. *p < 0.05 when compared to vehicle administered control mice

Fig. 3

Effects of GBR 12909 on exploratory behavior in 129/SvJ mice in the mouse BPM. Mice (129/SvJ) were administered various doses (5, 9, 10.9, 13.2, 16, and 28.5 mg/kg) of the selective DAT inhibitor GBR 12909 immediately prior to the assessment of their exploration in the mouse BPM. Exploration was measured in the BPM for activity levels—transitions (a), exploration—holepoking (b) and rearing (c), as well as locomotor patterns—spatial d (d). GBR 12909 increased activity at various doses tested, only 16 and 28.5 mg/kg initially but also 9, 10.9, and 13.2 mg/kg by the end of testing (a). The effects of GBR 12909 on exploration were similar for the two measures, with 16 and 28.5 mg/kg increasing holepoking (b) and rearing (c) toward the end of the test session. Doses of GBR 12909 larger than 10.9 mg/kg also lowered spatial d, although this effect was seen predominantly between 10 and 40 min (d). Data presented as mean ± SEM. *p < 0.05 when compared to vehicle administered control mice. Scales on the x-axes differ from Figs. 1 and 2 due to differing basal activity levels of C57BL/6J and 129/SvJ mice

Fig. 4

Time course of the effects of GBR 12909 on exploratory behavior in C57BL/6J mice in the mouse BPM. Mice were administered the selective DAT inhibitor GBR 12909 at various doses (9, 16, and 28.5 mg/kg) immediately prior a 3-h assessment of their exploration in the mouse BPM. Activity levels—transitions (a), exploration—holepoking (b) and rearing (c), as well as locomotor patterns—spatial d (d) were all measured. GBR 12909 increased activity at various doses tested, only 16 and 28.5 mg/kg initially but also 9 mg/kg throughout the 3-h period (a). Despite an initial drop in holepoking, GBR 12909 at 16 mg/kg consistently increased holepoking (b) and rearing (c). GBR 12909 at 16 mg/kg also consistently lowered spatial d (d), with some modest effects at 9 and 28.5 mg/kg as well. Data presented as mean ± SEM. *p < 0.05 when compared to vehicle administered control mice

Fig. 5

Representative actigrams from each study. The movement patterns of mice from each study are recorded and analyzed. These figures are representative patterns of movements from mice of each study. Patterns are from the 10–20-min time point of testing. As shown, amphetamine (a) and GBR 12909 administered (b) mice exhibit increased activity levels in the mouse BPM compared to their respective controls. The increased activity also led to more straight distance-covering behavior (lower spatial d) in these mice