Brain noradrenergic activity has been implicated in the regulation of cardiovascular (31) and endocrine(28) responses during exercise and in their adaptations to exercise and nonexercise stress after chronic exercise(44). Authors also have speculated that altered noradrenergic activity explains the reductions in major depression(40) and anxiety (32) reported by humans after exercise training. Such speculations are consistent with the established involvement of brain noradrenergic systems in the regulation of cardiovascular (30) and anterior pituitary hormone(48) responses to various stressors other than exercise and in the etiology of major depression (39) and anxiety disorders (35). Studies of acute physical activity and cross-sectional comparisons of groups differing in fitness have estimated brain noradrenergic activity by measuring 3-methoxy-4-hydroxyphenylglycol(MHPG) in urine (6,34,45,46,47) and plasma (46). Inferences about brain noradrenergic responses to exercise based on these studies are limited by the imprecision of peripheral NE and MHPG conjugates for measuring brain norepinephrine and its metabolism (37,38) and by the failure to quantify physical fitness or relative exercise intensity in most of the acute studies of MHPG (33).
We know of seven studies that examined changes in brain norepinephrine or MHPG concentrations after chronic exercise in rats(8,10,11,12,16,36,42). The independent effect of exercise cannot be determined from these studies because they confounded the exercise conditions with other stressors such as forced swimming, altered diet, or feeding schedules, injection, and electric shock (21) that influence brain noradrenergic responses(22). The exercise training stimulus was not controlled or a training effect was not measured in several of the studies, so it is important to determine whether NE adaptations with chronic exercise depend on other training adaptations (e.g., changes in the oxidative capacity of locomotory muscle). Adaptations may also differ in brain regions containing NE cell bodies (e.g., pons-medulla) compared with regions receiving ascending(e.g., frontal cortex and hippocampus) or descending (e.g., spinal cord) NE terminals. Also, we are aware of only two studies of chronic physical activity in the rat (10,42) that assessed both NE and MHPG, permitting the estimation of the extraneuronal metabolism of NE. A recent investigation (37) measured brain cortex levels of NE, MHPG, and 3,4- dihydroxyphenylglycol (DHPG), an estimate of the intraneuronal metabolism of NE (9,17,22), during acute running among treadmill trained rats; but we are unaware of studies assessing resting levels of DHPG after chronic exercise.
This study was designed to address the aforementioned issues by determining whether 8 wk of voluntary activity wheel running and treadmill exercise training would have comparable effects on regional brain concentrations of NE and its metabolites MHPG and DHPG assayed by liquid chromatography. Exercise training was indicated by succinate dehydrogenase activity assessed by enzymatic assay in soleus muscle. We expected both running conditions to have increased levels of NE and metabolites, with larger increases occurring in the treadmill training condition. We also examined whether the effects of wheel running and treadmill running on levels of NE, MHPG, and DHPG differed according to brain regions containing NE cell bodies (pons-medulla) and ascending (frontal cortex and hippocampus) and descending (spinal cord) terminal areas. The pons-medulla contains the locus coeruleus which accounts for about 60% of the cells that produce NE in the brain and is the sole known source of NE projected to the frontal cortex, and hippocampus, and a primary source of NE in the spinal cord (23).
MATERIALS AND METHODS
Animal Care and Training
Weanling (≈30 d of age) male Sprague-Dawley derived rats with a mean(±SD) mass of 57 ± 6 g were purchased from Charles River and were allowed to adapt to the vivarium for 2 d in individual polypropylene cages in a room maintained at 23 ± 1°C. Animals were kept in a constant light-dark cycle (light 0700-1900 h) with free access to rat chow and water. All procedures were in accordance with the guiding principles in the care and use of animals of the American College of Sports Medicine. After animals were adapted to individualized housing, they were familiarized with the exercise apparatus in an adjacent room by placing them on a motor driven treadmill (Stanhope, Davis, CA), at a speed that was graduated from 10 to 25 m·min-1 and from 5 to 15 min·d-1 without electric shock over a 13-d accommodation period. We anticipated a 20% subject loss from the beginning to the end of the training regimen, because of reports that about 10% of male Sprague-Dawley rats will not adapt to running on a treadmill(2) and some stop running after a period of training. In the present study 14% were excluded from the experiment during the adaptation period because they would not run. Previous reports have indicated no metabolic (7), endocrine (49). or behavioral (18) differences in rats that are willing to run and those that are not.
At the end of the adaptation period, 36 rats were randomly assigned to one of three experimental conditions lasting 8 wk: 1) 24-h access to an activity wheel (WR) provided the voluntary exercise condition. Daily distance(m·d-1) (mean ± SE) increased from 462 ± 104 to 2000 ± 1014 during weeks 1-3, stabilized at 2900 to 3375 ±≈1200 during weeks 4-7, and declined to 1254 ± 533 during week 8; 2) motorized treadmill running (TR) during the light phase at 0° incline for 30 min at 25-30 m·min-1 6 d·wk-1. Daily distance during weeks 1 and 2 was 624 ± 4 and 1183 ± 14, respectively. Treadmill running was gradually increased without electric shock to 25-30 m·min-1 for 60 min by the 3rd week of training and continued through week 8; distance ranged from 1580 ± 11 to 1790 ± 4. This protocol increases oxidative capacity, as measured by SDH activity, in slow oxidative soleus muscle fibers (2). Using the equation for level treadmill running of Armstrong and colleagues (3),˙VO2 was estimated to be 68 ml·kg-1·min-1 or between approximately 50% and 60%˙VO2peak. The control group (C) was sedentary, remaining in their home cages. All groups were handled and weighed daily in an equivalent manner. Final numbers of animals in each group were: WR, 10; TR, 11; C, 12.
After 8 wk of training, followed by 36 h of rest to allow neurotransmitter levels to achieve a steady state, animals were sacrificed by decapitation without anesthesia. All animals were sacrificed between 0730 and 0930 h to reduce the influence of circadian variability. The brain was removed and dissected over crushed ice according to the method of Glowinski and Iversen(24). Spinal cords were also removed according to the method of Yaksh and Harty (50). The dissected regions of the frontal cortex (without corpus striatum), hippocampus, pons-medulla, and all segments of the spinal cord were immediately frozen in liquid nitrogen within 3-5 min after decapitation. Tissues were stored at -80°C until assayed. Weighed samples were prepared by homogenizing in 6 ml of 0.1 N HClO4 using a mechanical homogenizer (Brinkman Polytron). All samples were kept cold (4°C) and centrifuged at 10,000 g for 20 min. Supernatants were divided into two 3-ml aliquots. One aliquot was used for the assay of MHPG and DHPG and the other for the assay of NE. To a separate 3-ml aliquot of 0.1 N HClO4, 500-μl (2.5 nmol) DHPG and 500-μl (0.5 nmol) MHPG-SO4 were added to serve as internal standards for the assay of MHPG and DHPG. Similarly 500-μl (1.25 nmol) 3,4-dihydroxybenzylamine(DHBA) in 3-ml HClO4 was used as internal standard for the NE assay. Standards were handled in the same manner as the samples from this point onward. Aliquots to be used for the NE assay were then frozen at -80°C until the time of the assay. The sensitivity of the assays at a 3:1 signal:noise ratio was 15 pg. In our laboratory the intra-assay variation for NE and DHPG is ≈5% and the recovery rates are 70-80%. The interassay coefficients of variation were: [NE], 9.6% at 12.5 pmol and 10.3% at 25 pmol; and [DHPG], 10.6% at 125 pmol and 9.2% at 250 pmol.
Because most of the MHPG in rat brain is sulfate-conjugated, samples were incubated with arylsulfatase and beta-glucuronidase for 16-20 h at 37°C for enzymatic hydrolysis of the sulfate conjugate. After hydrolysis and adjustment of the sample to pH 2-3 with 1.0 N NaOH, samples were purified by a Sephadex G-10 separation procedure (29). The sephadex column eluate was extracted with ethyl acetate, evaporated to dryness under nitrogen, and reconstituted with 200 μl of HPLC mobile phase. The reconstituted sample was then frozen and stored until injection onto the HPLC column. The interassay coefficient of variation for [MHPG] was 8.2% at 50 pmol and 6.9% at 125 pmol.
The HPLC system utilized a 5-μm Beckman C-18 reverse-phase column (4.6 mm i.d. × 15 cm length) that was coupled to a TL-5 glassy carbon working electrode (Bioanalytical Systems, West Lafayette, IN). An applied potential of 0.85 V was maintained at the working electrode relative to a Ag-AgCl reference. A mobile phase flow rate of 1.0 ml·min-1 was maintained. The mobile phase for the NE metabolites was composed of 0.1 M acetate buffer with 5% acetonitrile as the organic modifier (pH 5.3). The assay for NE was conducted according to the alumina column chromatographic procedure of Anton and Sayre (1). NE was eluted from the alumina column with 2 ml of 0.2 N acetic acid and 50 μl of this eluate was injected onto the HPLC column. The NE assay utilized the same Beckman C-18 reverse phase column that was employed for the assay of NE metabolites and the working electrode potential was maintained at 0.85 V versus the Ag-AgCl reference. The mobile phase flow rate was 1.0 ml·min-1. The mobile phase for NE analysis consisted of a 0.02 M citric acid-acetate buffer with the addition of EDTA (0.74 g·l-1) and 10 mg·l-1 sodium octyl sulfate. The pH was adjusted to 4.3 by the dropwise addition of acetic acid.
After decapitation, samples of soleus muscle were removed, immediately frozen in liquid nitrogen, and stored at -80°C until succinate dehydrogenase (SDH) activity could be assayed. SDH activities were measured after homogenization in 33 mM phosphate buffer (pH 7.4) by following cytochrome C reduction spectrophotometrically with succinate as substrate using procedures described by Cooperstein et al. (15).
The method of contrasts (SPSS-PC + 4.0, Chicago, IL) was used to compare the dependent variables between each experimental group and the sedentary control group and to compare the treadmill group with the activity wheel group, (P < 0.05). Pearson product-moment correlations were computed between brain regional levels of MHPG, DHPG, and NE and soleus muscle SDH activity for the WR group to determine whether dose-dependent relationships resulted from the variability in wheel running, (P< 0.05).
The mean (±SD) body mass was 58 ± 8.1 g at week 1 and 480± 37.0 g at week 11 (3 wk of adaptation and 8 wk of training). A 3-(group)-by-11 (wk) repeated measures ANOVA indicated a significant group-by-weeks interaction for body mass, F (20,330) = 3.51,P < 0.001. Duncan's post-hoc test indicated that body mass was the same among the groups until week 5. The mean mass of WR (286± 19.7 g) at week 5 was lower than TR (307 ± 16.5 g), but neither group differed from C (297 ± 12.5). This pattern continued through weeks 8 and 9 when the mass for WR (379 ± 36.1 and 405 ± 36.3, respectively) was lower compared with TR (417 ± 30.1 and 448± 31.3) and with C (415 ± 22.8 and 442 ± 28.2). Despite reduced wheel running by week 11, the mass for WR (457 ± 41.1) remained lower than C (502 ± 39.3) and TR (492 ± 39.4) at the end of training.
Brain norepinephrine and metabolite concentrations (mean ± SD) for each group are presented in Tables 1 and 2. Sample loss during the extraction procedures and the deletion of outlier responses according to Grubbs' criterion (43) are responsible for the unequal N among the groups.
In the frontal cortex, there were no differences among groups in [NE] or[DHPG], but [MHPG] was higher in TR compared with C, t(27) = 2.69,P < 0.01. Similarly in the hippocampus, there were no differences among groups for [NE] or [DHPG], but [MHPG] was higher in TR compared with C,t(13.7) = 1.85, P < 0.05.
In the pons-medulla, [NE] was higher compared with C for both TR,t(20) = 2.29, P < 0.05, and WR, t(20) = 1.78,P < 0.05. [DHPG] was higher in TR compared with C,t(14.7) = 2.13, P < 0.05. The groups did not differ in[MHPG]. In the spinal cord, [NE] was higher compared with C for both TR,t(22) = 2.57, P < 0.01, and WR, t(22) = 2.90,P < 0.01. There were no differences among groups in [MHPG] or[DHPG].
Cohen's (14) d-statistic (Mexp - Mc/SDc) was calculated to evaluate the strength of group differences (see Tables 1 and 2). Of the 17 statistically nonsignificant comparisons between conditions for the means of[NE], [MHPG], and [DHPG], 12 revealed higher levels for the running groups compared with controls. The average (mean ± SD) d-statistic for these 12 group differences was 0.63 ± 0.44, which is considered to be a moderate-to-large effect (14).
The mean SDH activities (μmol·min-1·g-1) in soleus muscle for TR (4.61 ± 0.79) were higher compared with WR (3.74± 0.82), t(30) = 2.30, P < 0.05, and with C(3.78 ± 0.96), t(30) = 2.36, P < 0.05. Pearson product-moment correlations were calculated in the WR condition between [NE],[MHPG], and [DHPG] in the brain areas and SDH activities in soleus muscle. Significant correlations were obtained for NE in the frontal cortex (r = 0.77) and for DHPG in the spinal cord (r = -0.77). The experimentwise Type I error rate associated with 12 correlation coefficients inflates an alpha of 0.05 to 0.46. Thus, we regard these two correlations as spurious.
Our finding that MHPG levels were increased in the frontal cortex and hippocampus in the treadmill running group suggests that extraneuronal metabolism of NE is increased in ascending brain noradrenergic terminal areas after treadmill training. In contrast, the increased NE levels, with unchanged MHPG levels, in the spinal cord and in the pons-medulla after both treadmill training and wheel running suggests no change or a reduction in noradrenergic metabolism from extraneuronal sources in these regions. Our findings may reflect a decreased stimulation of sensory or sympathetic motor neurons in the spinal cord by descending noradrenergic neurons, consistent with the tissue-specific decreases in peripheral noradrenergic activity reported after chronic exercise in some studies (31,44). However, the meaning of the increased NE and DHPG in the pons-medulla is unclear since most synthesis and storage of NE occurs in NE terminals. DHPG is derived in part from deamination of released NE after reuptake by the NE neuron, thus increased DHPG can indicate increased release of NE in terminal areas(22,37). Increased DHPG in the pons-medulla after treadmill training is compatible with increased autoactivity of NE neurons(22) which would decrease NE synthesis and the discharge rate of NE neurons or with an altered path of intraneuronal metabolism of NE.
Acute treadmill running is accompanied by a 50% increase in microneurographic discharge above active waking in locus coeruleus cell bodies of cats compared with a 300% to 600% increase during morphine-induced emesis and tail pinch, respectively (41). Hence, NE activity in NE neurons should differ to the extent that locomotion is aversive(26). Since NE levels in the pons-medulla and spinal cord were increased similarly after treadmill training and voluntary wheel running in the present study, it is possible that locomotory influences on NE activity are similar for each mode of exercise but that supramedullary responses are unique to treadmill training. To our knowledge, however, studies of brain noradrenergic nerve discharge during exercise have not been reported in the rat. We previously reported that rats that were treadmill trained or chronically ran in an activity wheel maintained NE levels in microdissected cell bodies of the locus coeruleus after immobilization stress(19) and footshock (20), which were similar to levels in homecage nonstressed controls, contrasted with lowered NE levels after stress in sedentary animals.
Our findings extend previous studies reporting increases in whole brain NE concentrations after treadmill training (11), forced swimming (36), and operant wheel running(12,16), by indicating brain regional specificity in NE levels. Such specificity agrees with previous studies reporting that NE and MHPG levels varied according to brain region, but those studies confounded exercise with other stressors known to elicit noradrenergic responses(13,21). In a study of activity wheel exercise, Rea and Hellhammer (42) found an increase in MHPG in the frontal cortex but did not observe increased hippocampal MHPG levels. A comparison of their results with our findings is ambiguous because they used food deprived animals. Ostman and Nyback (36) observed increased whole brain NE in animals subjected to swim stress, which can be confounded by cold stress with exertion (25). Brown and Van Huss (12) reported increased NE in whole brain after chronic wheel running operantly conditioned using electric shock and in whole brain and cortex after treadmill training mixed with a high fat diet(11). Blomstrand et al. (8) found no change in NE levels in the hippocampus or pons-medulla at rest or after acute running in female Wistar rats using a reversed-phase treadmill training protocol similar to the one we used in the present study.
The treadmill running protocol we employed was successful in eliciting a training adaptation indicated by increased soleus SDH activity comparable to past reports (3). Since the SDH activity of the wheel running group did not differ from that of the control animals, our study permits a partial test of whether brain noradrenergic adaptations appear dependent on an exercise training effect. However, we (unpublished observations) have found training effects for citrate synthase activity in soleus muscle after wheel running. Thus, the decreased wheel running during the final 2 wk of the present study may have precluded the detection of a training adaptation at the longer distances observed earlier in the study. Although running distance was variable in the wheel group, noradrenergic changes were not correlated with soleus muscle SDH activity. Nonetheless, the larger and more consistent neurotransmitter effects occurring in the treadmill trained group suggest an exercise dose-dependent relationship with brain noradrenergic metabolism that is specific to brain region. The larger effects for MHPG levels in the frontal cortex, hippocampus, and pons-medulla for the treadmill running group (Cohen's d, ≈1.65) compared with increased MHPG in the frontal cortex and hippocampus (d, ≈0.90), with no effect in the pons-medulla, for the activity wheel running group also suggests an exercise dose-response relationship that may be dependent on exercise intensity rather than running distance. Similarly, the effect for NE in the frontal cortex was large (d, ≈0.70) for the treadmill group but small (d, ≈0.25) for the wheel group. A direct test of a dose-response relationship for brain NE and metabolites with exercise training will require that the same activity mode be used with different intensities and/or durations of exercise.
Our results suggest that voluntary and forced running do not produce equivalent brain noradrenergic changes. Prior investigation indicated that the type of stressor can moderate tyrosine hydroxylase (TH) activity in sympathetic ganglia and the adrenal gland (27), and it appears that peripheral synthesis and turnover of NE after exercise training is specific to end-organs, differing in heart, liver, and adrenal tissue(31). It will be important to determine which sympathetic ganglia are being activated during exercise to understand adaptations in nerve traffic between the peripheral sympathetic nervous system and the spinal cord and brain in response to exercise. Levels of DHPG and MHPG are conventionally used as estimates of intra- and extra-neuronal metabolism, respectively(4,9,17). However, direct measures of NE release, synthesis, and turnover are needed to determine the neural mechanisms responsible for the differences in levels of NE, MHPG, and DHPG that we report. Nonetheless, our results suggest target areas in the brain and spinal cord for direct studies of NE release during acute running (e.g., using microdialysis). We know of one report using microdialysis that indicated increased release of NE, followed by increased MHPG and DHPG, in the frontal cortex after acute treadmill running (37). Measuring the activity of tyrosine hydroxylase, the rate limiting enzyme in NE synthesis, in brain regions can clarify the meaning of the changes in NE and metabolites that we report. Changes in adrenoreceptor-effector systems may also be informative. One study in which wheel running was operantly conditioned by a feeding schedule reported no change in brain hemispheric β-adrenoreceptor density despite an increase in NE levels of nearly one-and-onehalf standard deviation (16).
Future studies should determine whether chronic exercise increases turnover and storage of brain NE differentially according to brain region and if concentrations of NE, MHPG, and DHPG can estimate NE flux under exercise conditions. Because pharmacologic blockade of NE reuptake and autoactivity can chronically alter the activity of metabolic enzymes for NE(5), rate-limiting enzymes for the synthesis and metabolism of NE will provide other estimates of noradrenergic activity following exercise.
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Keywords:©1996The American College of Sports Medicine
HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; EXERCISE; MHPG; DHPG