Exercise-Induced Adaptations to the Mouse Striatal Adenosine System

Abstract

Adenosine acts as a key regulator of striatum activity, in part, through the antagonistic modulation of dopamine activity. Exercise can increase adenosine activity in the brain, which may impair dopaminergic functions in the striatum. Therefore, long-term repeated bouts of exercise may subsequently generate plasticity in striatal adenosine systems in a manner that promotes dopaminergic activity. This study investigated the effects of long-term voluntary wheel running on adenosine 1 (A₁R), adenosine 2A (A_2AR), dopamine 1 (D₁R), and dopamine 2 (D₂R) receptor protein expression in adult mouse dorsal and ventral striatum structures using immunohistochemistry. In addition, equilibrative nucleoside transporter 1 (ENT1) protein expression was examined after wheel running, as ENT1 regulates the bidirectional flux of adenosine between intra- and extracellular space. The results suggest that eight weeks of running wheel access spared age-related increases of A₁R and A_2AR protein concentrations across the dorsal and ventral striatal structures. Wheel running mildly reduced ENT1 protein levels in ventral striatum subregions. Moreover, wheel running mildly increased D₂R protein density within striatal subregions in the dorsal medial striatum, nucleus accumbens core, and the nucleus accumbens shell. However, D₁R protein expression in the striatum was unchanged by wheel running. These data suggest that exercise promotes adaptations to striatal adenosine systems. Exercise-reduced A₁R and A_2AR and exercise-increased D₂R protein levels may contribute to improved dopaminergic signaling in the striatum. These findings may have implications for cognitive and behavioral processes, as well as motor and psychiatric diseases that involve the striatum.

Figure 1

Striatal A₁R and A_2AR protein expression following three or eight weeks of wheel running. Representative immunohistochemistry images for A₁R in the mouse striatum following eight weeks of (a) sedentary conditions and (b) running wheel access. (c) Relative levels of A₁R protein density represented as averages across sections as detailed in the Methods. Representative immunohistochemistry images for A_2AR in the mouse striatum following eight weeks of (d) sedentary conditions and (e) running wheel access. (f) Relative levels of A_2AR protein density represented as averages across sections as detailed in Methods. Statistical significance denoted as follows: sedentary 8 weeks vs. runner 8 weeks at ^Ap < 0.05, ^Bp < 0.01, and ^Cp < 0.001. Sedentary 8 weeks vs. runner 3 weeks at ^Dp < 0.05, ^Ep < 0.01, and ^Fp < 0.001. Sedentary 8 weeks vs. sedentary 3 weeks at ^Gp < 0.05, ^Hp < 0.01, and ^Ip < 0.001. Runner 8 weeks vs. sedentary 3 weeks at ^Jp < 0.05. Runner 8 weeks vs. runner 3 weeks at ^Kp < 0.05 and ^Lp < 0.01. Sedentary 3 weeks vs. runner 3 weeks at ^Mp < 0.05.

Figure 2

Striatal ENT1, D₂R, and D₁R protein expression following eight weeks of wheel running. Representative immunohistochemistry images for ENT1 in the mouse striatum following eight weeks of (a) sedentary conditions and (b) running wheel access. (c) Relative levels of ENT1 protein density represented as averages across sections as detailed in Methods. Representative immunohistochemistry images for D₂R in the mouse striatum following eight weeks of (d) sedentary conditions and (e) running wheel access. (f) Relative levels of D₂R protein density represented as averages across sections detailed in Methods. Representative immunohistochemistry images for D₁R in the mouse striatum following eight weeks of (g) sedentary conditions and (h) running wheel access. (i) Relative levels of D₁R protein density represented as averages across sections as detailed in Methods. Sedentary 8 weeks vs. runner 8 weeks at ^Ap < 0.05 and ^Bp < 0.01.