Chronic voluntary exercise induces plasticity of noradrenaline-activated dopamine D1-like receptor signaling

Abstract

Physical exercise has lasting positive influence on mental health. However, its cellular substrate remains to be elucidated. Recently, dopamine D₁-like receptor activation induced by noradrenaline has been suggested to underlie exercise-dependent augmentation of antidepressant effects. The present study demonstrates that exercise induces a long-term enhancement of this atypical catecholaminergic signaling. Noradrenaline potentiates hippocampal mossy fiber synaptic transmission by activating D₁-like receptors in mice. Voluntary exercise by wheel running enhanced this noradrenaline-D₁-like receptor signaling within 5 days. The enhancement of the noradrenaline-D₁-like receptor signaling did not require the integrity of noradrenergic fibers and was maintained for more than 2 weeks after cessation of wheel running. Notably, the effect of exercise was more robustly seen in D₁-like receptor signaling activated by noradrenaline as compared with dopamine, indicating particular responsiveness of the noradrenaline-activated D₁-like receptor signaling to exercise. These results suggest that exercise could exert lasting influence on brain functioning via plasticity of the hippocampal noradrenaline-D₁-like receptor signaling.

Keywords: Dopamine; Exercise; Hippocampus; Mossy fiber; Noradrenaline.

Fig. 1

Enhancement of noradrenaline-D₁-like receptor signaling by exercise. a Potentiation of EPSPs at the MF synapse by noradrenaline (10 µM) in control mice (CNT) and after 2 weeks of wheel running (WR). Noradrenaline was applied at the bar in the presence of propranolol (10 µM). In some experiments, SKF83566 (SKF, 200 nM) was supplemented. Sample recordings show averaged field EPSPs before and during noradrenaline application (scale bars: 10 ms, 0.2 mV). b Enhancement of noradrenaline-induced synaptic potentiation depends on duration of WR (Day5: Welch’s correction, t_7.572 = 3.635, **P = 0.0073; Day7: t₁₃ = 3.159, **P = 0.0075; Day14: t₁₄ = 6.259, ****P < 0.0001). See f for statistics of Day28. c Effects of 2 weeks of WR on synaptic potentiation induced by dopamine (5 µM). Recordings were made in the absence of propranolol. d Enhancement of dopamine-induced synaptic potentiation by WR (t₁₅ = 2.612, *P = 0.0196), and a larger effect of WR on noradrenaline-induced synaptic potentiation (two-way ANOVA: substance × WR interaction, F_1,29 = 5.184, #P = 0.0304). Noradrenaline data are same as those of Day14 in b. e Noradrenaline-induced synaptic potentiation after removal of running wheel. f Significant enhancement of noradrenaline-induced synaptic potentiation maintained after cessation of WR. The data of CNT and WR are same as those of Day28 in b. One-way ANOVA (F_{2, 21} = 16.68, P < 0.0001) followed by Tukey’s test (*P = 0.0141, **P = 0.0072, ****P < 0.0001). g A transient increase in nocturnal home cage activity after wheel running exercise. h Effects of WR on noradrenaline-induced synaptic potentiation in mice treated with DSP-4 (50 mg/kg) (t₈ = 5.632, ***P = 0.0005). i DSP-4 augments synaptic potentiation induced by a lower concentration (3 µM) of noradrenaline and occludes the effect of the noradrenaline uptake inhibitor nisoxetine (Niso, 1 µM). Mice subjected to 2 weeks of WR were used. Two-way ANOVA (DSP-4 effect: F_1,19 = 16.35, P = 0.0007; Niso effect: F_1,19 = 38.53, P < 0.0001; interaction: F_1,19 = 7.586, P = 0.0126) followed by Tukey’s test (***P = 0.0005, ****P < 0.0001, NS: not significant). All data are presented as means ± SEM with or without individual values. The number of data shown in parentheses represents the number of mice in g and slices in other panels