Reduced effects of age on dopamine D2 receptor levels in physically active adults
Introduction
Increasing evidence indicates that physical activity has broad benefits for physical health, mental health, and cognitive function across the life span (Kramer and Erickson, 2007). Widespread public health efforts, led by a coalition of national organizations, including the National Institute on Aging and the Center for Disease Control and Prevention, seek to increase physical activity among America's aging population with the intention of, among other stated benefits, sustaining neurotransmitter levels and functional capacity (Sheppard et al., 2003). The dopamine system (Nieoullon, 2002), for which there is extensive evidence of age-related decline in dopamine D1 receptors, D2 receptors (DRD2), and transporters, is strongly implicated in a range of cognitive functions from reward processing to cognitive control (Backman et al., 2006). Thus, any intervention that slows the rate of age-related decline in dopamine functioning should generally promote cognitive health.
Most research examining the causal role of physical activity on dopamine function has been performed in rodents treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), a neurotoxin that kills dopamine neurons. Physical activity prior to MPTP treatment was found to protect mice against MPTP-induced neurotoxicity (Gerecke et al., 2010). After MPTP treatment, physical activity increased the number of dopamine neurons, normalized axonal and dendritic arborization, and increased DRD2 expression (Ahmad et al., 2009, Vuckovic et al., 2010). Physical activity is believed to protect dopamine function by inhibiting inflammation-induced dopaminergic degeneration via suppression of microglial activity or activation of the brain-derived neurotrophic factor signaling pathway (Sung et al., 2012, Wu et al., 2011).
Intriguingly, exercise training was observed to increase striatal DRD2 receptor availability in humans with Parkinson's disease and methamphetamine users (Fisher et al., 2013, Robertson et al., 2016). However, although aging, Parkinson's disease, methamphetamine use and MPTP neurotoxicity all impact dopamine functions, the specificity of their effects on the dopamine system differs significantly. Degeneration associated with Parkinson's disease is much steeper than during normal aging, and dopamine loss in Parkinson's disease is much greater in the putamen than the caudate, whereas in normal aging dopamine loss is approximately equivalent in both striatal structures (Kish et al., 1992, Kumakura et al., 2010). Therefore it remains unknown whether these findings from degenerative and neurotoxic conditions can be extrapolated to disease-free humans.
In a cross-sectional study, we examined whether physical activity is associated with reduced age effects on DRD2 receptors. Forty-four healthy human subjects (27 females) between 23 and 80 years old underwent PET with [18F]fallypride, a high affinity DRD2 ligand (Siessmeier et al., 2005) for the assessment of DRD2 availability, underwent structural MRI to aid coregistration of PET data during data processing, and wore a pedometer for 10 consecutive days to measure the number of steps each subject took per day as an assessment of regular physical activity. Binding potential (BPND) images, reflecting DRD2 availability, were calculated from PET [18F]fallypride data using the simplified reference tissue model. Striatal (caudate, putamen, ventral striatum / nucleus accumbens) and midbrain regions of interest were defined in standard MNI space using previously published guidelines (Dang et al., 2012a, Mawlawi et al., 2001) and nonlinearly registered to each subject's BPND image for BPND extraction (Fig. 1).
Section snippets
Subjects
Fifty-three healthy volunteers from the Nashville, TN metro area participated in this study. The present report included data from 44 subjects (23 to 80 years old, mean age±SD: 48 ± 16 years, 27 females) (see the Physical Activity Assessment section for details on the exclusion of 9 subjects from analyses). Exclusion criteria included any history of psychiatric illness on a screening interview (a Structural Interview for Clinical DSM-IV Diagnosis was also available for all subjects and
Results
To counteract the issue of multiple comparisons with 4 ROIs, we applied Bonferroni correction and utilized a corrected significance threshold of p<0.0125. As expected, we found that age (mean±SD: 48±16 years) negatively correlated with BPND in all three regions of the striatum, which has the highest concentration of postsynaptic DRD2 in the brain, as well as in the midbrain, the site of dopamine neurons on which presynaptic DRD2 are located: caudate (r42=–0.839, p<0.0001), putamen (r42=–0.695,
Discussion
These results provide in vivo evidence supporting a positive association between regular physical activity and postsynaptic DRD2 availability in healthy disease-free human adults. Consistent with previous literature, postsynaptic DRD2 availability was negatively associated with age (Rinne et al., 1993). Using the high affinity radiotracer [18F]fallypride, we extended these findings, showing that there is also significant loss of presynaptic DRD2 in the midbrain, which may reflect either
Conflict of interest
none.
Acknowledgments.
This work was supported by the National Institute on Aging (R01AG044838 to DHZ, R00AG042596 to GRSL) and the National Institute on Drug Abuse (F32DA036979 to LCD). Funding institutes were not involved in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. Thanks to Kruti Vekaria for assistance with data collection.
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