Pharmacological manipulation of the dopaminergic system affects wheel-running activity in differentially active mice

Abstract

The genetic factors involved in the regulation of physical activity are not well understood. The dopamine system has been implicated in the control of voluntary locomotion and wheel running (WR) in mice and is thus a likely candidate as a genetic/biological system important to the regulation of physical activity. This study evaluated the effects of four different dopaminergic acting drugs on WR in differentially active inbred strains of mice. High active C57L/J (n=7, 3 controls, 4 experimental) and low active C3H/HeJ (n=8, 3 controls, 5 experimental) were analyzed for baseline wheel-running indices of distance (km/day), duration (mins/day), and speed (m/min) for 21 days. Experimental mice received increasing doses over four days of each of the following drugs: SKF 81297 (D1 agonist), SCH 23390 (D1 antagonist), GBR 12783 (DAT inhibitor), and AMPT (tyrosine hydroxylase inhibitor). Each drug dose response treatment was separated by three days of recovery (no drug injections). WR indices were monitored during drug treatments and during drug wash-out phases. SKF 81297 significantly reduced (p=0.0004) WR in the C57L/J mice, but did not affect WR in the C3H/HeJ mice. GBR 12783 significantly increased (p=0.0005) WR in C3H/HeJ mice, but did not affect WR in C57L/J mice. Only duration (not overall WR) was significantly reduced in C57L/J mice in response to SCH 23390 (p=0.003) and AMPT (p=0.043). SCH 23390 (p=0.44) and AMPT (p=0.98) did not significantly affect WR in C3H/HeJ mice. These results suggest that genetic differences in dopamine signaling may play a role in the WR response to dopaminergic-acting drugs in inbred strains of mice. The high activity in the C57L/J strain appears most responsive to D1-like receptor acting drugs, while in the C3H/HeJ strain, dopamine re-uptake appears to have an influence on activity level.

Fig. 1

Baseline values of distance, duration, and speed in control and experimental mice. A) Running wheel data at baseline for C57L/J mice (n=7) is shown. No differences in distance (km) (p=0.52), duration (mins) (p=0.52), or speed (m/min) (p=0.74) were found between control and experimental groups; however, C57L/J mice ran significantly farther, longer, and faster than C3H/HeJ mice at baseline (p<0.0001). B) Running wheel data at baseline for C3H/HeJ mice (n=8). No differences in distance (p=0.22), duration (p=0.23), or speed (p=0.44) were found between control and experimental groups.

Fig. 2

Distance responses to all four dopaminergic drugs in C57L/J mice. Distance responses to all four drugs in the C57L/J mice. A) Dose response after administration of SKF 81297 is shown. No significant dose response was seen; however, all four doses significantly reduced wheel running distance in experimental mice compared to controls (p=0.0004). B) Dose response to SCH 23390 is shown. No significant changes in distance run between groups were seen for any dose (p=0.12). C) Dose response to GBR 12783 is shown. No significant differences in distance run were seen between groups for any dose (p=0.89). D) Dose response to AMPT is shown. No significant differences in distance run between grousp were seen for any of the doses (p=0.37).

Fig. 3

Distance responses to all four dopaminergic drugs in C3H/HeJ mice. Distance responses to all four drugs in the C3H/HeJ mice. A) Dose response after administration of SKF 81297 is shown. No significant differences in distance between groups were seen for any dose (p=0.91). B) Dose response to SCH 23390 is shown. No significant changes in distance run between groups were seen for any dose (p=0.44). C) Dose response to GBR 12783 is shown. No significant dose response was observed, however, distance was significantly increased in the experimental group compared to control following treatment with all four doses (p=0.0005). D) Dose response to AMPT is shown. No significant differences in distance run between group were seen for any of the doses (p=0.98).