Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway

Abstract

The mesolimbic reward pathway is implicated in stress-related psychiatric disorders and is a potential target of plasticity underlying the stress resistance produced by repeated voluntary exercise. It is unknown, however, whether rats find long-term access to running wheels rewarding, or if repeated voluntary exercise reward produces plastic changes in mesolimbic reward neurocircuitry. In the current studies, young adult, male Fischer 344 rats allowed voluntary access to running wheels for 6 weeks, but not 2 weeks, found wheel running rewarding, as measured by conditioned place preference (CPP). Consistent with prior reports and the behavioral data, 6 weeks of wheel running increased ΔFosB/FosB immunoreactivity in the nucleus accumbens (Acb). In addition, semi quantitative in situ hybridization revealed that 6 weeks of wheel running, compared to sedentary housing, increased tyrosine hydroxylase (TH) mRNA levels in the ventral tegmental area (VTA), increased delta opioid receptor (DOR) mRNA levels in the Acb shell, and reduced levels of dopamine receptor (DR)-D2 mRNA in the Acb core. Results indicate that repeated voluntary exercise is rewarding and alters gene transcription in mesolimbic reward neurocircuitry. The duration-dependent effects of wheel running on CPP suggest that as the weeks of wheel running progress, the rewarding effects of a night of voluntary wheel running might linger longer into the inactive cycle thus providing stronger support for CPP. The observed plasticity could contribute to the mechanisms by which exercise reduces the incidence and severity of substance abuse disorders, changes the rewarding properties of drugs of abuse, and facilitates successful coping with stress.

Figure 1

(A) Mean distance (km) run each day by adult male Fisher 344 rats allowed voluntary access to running wheels. Rats included in the first experiment (Exp 1) were used for CPP behavioral testing and had voluntary access to running wheels every other night. Rats in experiment 2 (Exp 2) and experiment 3 (Exp 3) were used for immunohistochemistry and in situ hybridization, respectively, and had nightly voluntary access to running wheels. (B) Mean hourly distance run (m) during the first, second, and sixth week of voluntary wheel access. Values represent group means ± standard error of measurement.

Figure 2

(A) Experimental timeline for the conditioned place preference (CPP) experiment (Exp 1). Following a baseline preference (probe) test (BL), rats (n = 8) had alternating nightly access to running wheels or locked wheels for 6 weeks. During CPP training, wheel running was paired (30 minutes) with one side of the chamber and the absence of wheel running was paired with the opposite side on alternating mornings. Ten minute CPP probe tests occurred following 2 (probe test A) or 6 (probed test B) weeks of CPP training. Following probe test B at the end of the 6^th week of wheel running, wheels were locked and rats underwent extinction training during which rats were exposed to the paired side, in the absence of running, daily for 30 minutes / day. A probe test occurred 24 hr following the final extinction training trial (probe test C). (B) Preference (± standard error of measurement) for the side of the CPP chamber paired with wheel running observed during the 10 minute probe tests. *p < .05 compared to all other groups.

Figure 3

(A) Photomicrograph (10X magnification) of ΔFosB/FosB immunoreactivity in the nucleus accumbens (Acb) of a sedentary rat. Boxes represent areas analyzed. AcbC, nucleus accumbens core; AcbS, nucleus accumbens shell; ac, anterior commisure. (B) Number of ΔFosB/FosB positive cells in the Acb core and shell following 6 weeks of voluntary wheel running (exercised; n = 7) or sedentary housing with a locked wheel (n = 8). Values represent mean number of positive cells ± standard error of measurement. * p < .05, ** p < .01, *** p<.001 with respect to Sedentary group at that level.

Figure 4

(A) Relative levels of tyrosine hydroxylase (TH) messenger ribonucleic acid (mRNA) in the rostral to caudal subregions of the ventral tegmental area (VTA) of sedentary rats housed with a locked wheel (Sedentary; n = 9) or rats allowed access to a running wheel for 6 weeks (Exercised; n=10). Values represent mean integrated density ± standard error of measurement. * p < .01 with respect to Sedentary. Representative autoradiographs showing in situ hybridization for TH mRNA in the VTA of sedentary (B) and exercised (C) rats.

Figure 5

(A) Relative levels of dopamine receptor (DR)-D2 messenger ribonucleic acid (mRNA) in the rostral to caudal subregions of the nucleus accumbens (Acb) of animals allowed access to a running wheel for 6 weeks (Exercised; n=10) or housed under sedentary, locked wheel, conditions (Sedentary; n=9). Values represent mean integrated density ± standard error of measurement. * p<.05 with respect to Sedentary. Representative autoradiographs showing in situ hybridization for DR-D2 mRNA in the Acb of sedentary (B) and exercised (C) rats. CPu, caudate putamen.

Figure 6

(A) Relative levels of delta opioid receptor (DOR) messenger ribonucleic acid (mRNA) in the rostral to caudal subregions of the nucleus accumbens (Acb) of sedentary rats (Sedentary; n = 9) or rats allowed voluntary access to running wheels for 6 weeks (Exercised; n=10). Values represent mean integrated density ± standard error of measurement. * p<.05 with respect to Sedentary. Representative autoradiographs showing in situ hybridization for DOR mRNA in the Acb of sedentary (B) and exercised (C) rats. CPu, caudate putamen.