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00005768-199701000-0001000005768_1997_29_63_dishman_monoamines_1report< 145_0_8_9 >Medicine & Science in Sports & Exercise©1997The American College of Sports MedicineVolume 29(1)January 1997pp 63-74Brain monoamines, exercise, and behavioral stress: animal models[Basic Sciences: Symposium: Exercise, Brain and Behaviour]DISHMAN, ROD K.Section Editor(s): Dishman, Rod K. ChairDepartment of Exercise Science, The University of Georgia, Athens, GA 30602-3654Received for publication February 1996.Accepted for publication June 1996.Thanks go to my colleagues who coauthored the papers discussed herein and to my students, Andrea Dunn, Jaimie Warren, Ho Sang Yoo, Shawn Youngstedt, and Jill White-Welkley, for doing the work.Address for correspondence: Rod K. Dishman, Ph.D., Department of Exercise Science, Ramsey Student Center, The University of Georgia, 300 River Road, Athens, GA 30602-3654. E-mail: paper summarizes our studies examining whether changes in levels of brain monoamines after chronic exercise are associated with altered behavioral and endocrine responses to stressors other than exercise. The focus is on using animal models relevant for understanding reports by humans that regular physical activity reduces depression and anxiety. We studied the effects of chronic activity wheel running or treadmill exercise training on levels of norepinephrine (NE) measured in brain cell bodies and terminal regions at rest and after behavioral stress. We also measured brain levels of serotonin, i.e., 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma aminobutyric acid (GABA), which function as both antagonists and synergists with NE. In general, we found that chronic activity wheel running increased NE levels in the pons medulla at rest and protected against NE depletion in locus coeruleus cell bodies after footshock: the concomitant reduction in escape-latency was consistent with an antidepressant effect. Wheel running also decreased the density of GABAA receptors in the corpus striatum while increasing open-field locomotion, consistent with an anxiolytic effect, but had no effect on hypothalamic-pituitary-adrenal cortical response to footshock measured by plasma levels of adrenocorticotropic hormone (ACTH), corticosterone, and prolactin. In contrast, treadmill exercise training increased the metabolism of NE in brain ascending terminal areas for NE, increased the secretion of ACTH after footshock and immobilization stress and had no effect on GABAA receptor density or open field locomotion. The validity of animal models for studying depression and anxiety after forced versus voluntary exercise is discussed. Recommendations are offered for improving the methods used in this area of research.It is not known whether chronic physical activity alters the way the brain regulates behavioral and endocrine responses to stressors other than exercise (59). Animal models permit the experimental manipulation of such responses to determine whether they are relevant for understanding the antidepressant and antianxiety effects of regular physical activity reported by humans. However, animal models have received little use for this purpose in exercise science (43). Among humans, social determinants of stress interact with differences among people in their appraisal of the meaning of events and how they cope with this appraisal or its consequences (33). Hence, advocates of a biological approach using animal models to understand behavioral disorders must recognize that the meaning of biological adaptations to explain the human experience of stress-related depression and anxiety cannot be fully understood unless behavior, environmental context, and phenomenology (e.g., self report) are measured concomitantly with biology. Thus, animal models are inherently limited for drawing inferences about human experience. Nonetheless, the nearly exclusive use of social-cognitive models of stress in past studies of physical activity, depression, and anxiety in humans has limited our understanding in this area (42), justifying the accelerated use of animal models.Our research has examined regional changes in levels of norepinephrine (NE) in the brain after chronic exercise, as well as brain serotonin, i.e., 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma aminobutyric acid (GABA), which function as both antagonists and synergists with NE. NE was the first substance identified as a mediator of peripheral nerve cell activity(32), but it was not until 50 years later that NE neurons were located in the brain (11,68). NE comprises only about 1% of the brain's neurotransmitters, and like 5-HT and DA, its actions are slower than classic neurotransmitters such as GABA(seconds rather than milliseconds). However, NE neurons are diffuse and topographically organized in the brain (see Fig. 1) and peripheral nervous system, and NE is recognized as a major modulator of brain neural activity (23). The pons medulla contains the locus coeruleus (LC), which accounts for 50-60% of the cells that produce NE in the brain and is the sole known source of NE projected to the frontal cortex, hippocampus, thalamus, and cerebellum and a primary source of NE in the hypothalamus, amygdala, and spinal cord (24). Inhibitory NE neurons also project to 5-HT cell bodies in the dorsal raphe. Each of these regions is involved in integrating behavioral responses during stress. There is scientific consensus that brain noradrenergic neurons modulate a wide range of functions, including pituitary hormone release, cardiovascular function, sleep, and analgesic responses(10).Figure 1-Monoamine neural pathways in the rat brain from the dorsal view. The serotoninergic, i.e., 5-hydroxytryptamine, system is on the left. The noradrenergic and dopaminergic systems are on the right. Reprinted with permission from Elliot, G. R., et al. Indoleamines and other neuroregulators. In: Psychopharmacology: From Theory to Practice, J. D. Barchas et al. (Eds.). New York: Oxford University Press, pp. 33-50, 1977.Authors have speculated that altered noradrenergic activity explains the reductions in major depression (52) and anxiety(41) reported by humans after chronic exercise. Although such speculations are consistent with the established involvement of brain noradrenergic systems in the regulation of cardiovascular(30) and anterior pituitary hormone(49) responses to various stressors other than exercise and in the etiology of major depression (51) and anxiety disorders (45), supporting evidence from exercise studies has been virtually nonexistent.Early studies using rats showed that acute cold exposure and treadmill running led to decreased brain NE in LC and its terminal areas(3,60), but chronic exercise appeared to increase NE or its metabolites in several brain areas (9). Hence, our research began with the hypothesis that chronic physical activity alters the brain noradrenergic system in a way qualitatively similar to pharmacotherapy for major depression. Typical antidepressant drugs downregulate the β-adrenoreceptor-effector and upregulate theα-adrenoreceptor-effector, concomitantly with a normalization of NE levels and neural function in rats (2).However, little was known about whether acute responses or chronic adaptations by brain NE systems after exercise were similar to those observed after pharmacotherapy or acute and chronic exposure to nonexercise stressors. During acute nonexercise stress there are concomitant increases in noradrenergic neurons of 3,4-dihydroxyphenylglycol (DHPG), the deaminated intraneuronal metabolite of NE, consistent with increased NE release, and decreases in dihydroxyphenylacetic acid (DOPAC), the deaminated intraneuronal metabolite of dopamine, consistent with reduced conversion of dopamine to NE by dopamine β-hydroxylase in storage vesicles (23). The depletion of NE during acute nonexercise stress appears to result from insufficient synthesis of NE (beyond the rate-limiting step of tyrosine hydroxylation) to keep pace with the release of NE. Conversely, chronic (14-30 d) intermittent stress by footshock or immobilization is accompanied by a decrease in cyclic AMP accumulation in the presence of NE and reduced density of β1-adrenoreceptors in brain slices, indicating a postsynaptic downregulation of the receptor-effector for NE (61). At the same time, chronic stress leads to increased activity of tyrosine hydroxylase, indicative of increased synthesis of DA and NE, and compensatory storage of NE in the hippocampus and frontal cortex of the brain, areas where LC neurons terminate (23). In contrast, the effects of physical activity on NE synthesis or storage in the brain and on β-(12,76) and α-adrenoreceptors in the brain have received little study, especially as they relate to models of depression or anxiety.CHRONIC EXERCISEPrior to our first investigation, we located seven studies that examined changes in resting brain NE or 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations following chronic exercise in rats (20). Whether exercise had an independent effect on NE could not be determined from these studies because they typically confounded the exercise conditions with other stressors such as forced swimming, altered diet or feeding schedules, injection, and electric shock that influence brain noradrenergic responses(23). The exercise training stimulus was not controlled or a training effect was not measured in several studies; this is important since NE adaptations with chronic exercise might depend on other training adaptations (e.g., changes in the oxidative capacity of locomotory muscle). Also, most studies measured levels of NE in the whole brain rather than in specific brain regions. Studies using stressors other than exercise have indicated that noradrenergic activity differs in brain regions depending upon the type of stressor (22,44,63). Also, only two studies of chronic physical activity in the rat(6,54) assessed both NE and MHPG, permitting the estimation of the extraneuronal metabolism of NE. None had assessed DHPG, permitting the estimation of the intraneuronal metabolism of NE.Our first study (21) was designed to determine whether 8 wk of voluntary activity wheel running or forced treadmill exercise training would have similar effects on brain concentrations of NE and its metabolites MHPG and DHPG assayed by high performance liquid chromatography with electrochemical detection (HPLC-EC). Exercise training was verified by changes in the oxidative capacity of locomotory muscle. We also examined whether the effects of wheel running or treadmill running on levels of NE, MHPG, and DHPG differed according to brain regions containing NE cell bodies(pons medulla), where the primary regulation of NE synthesis and nerve discharge occurs, and ascending (frontal cortex and hippocampus) and descending (spinal cord) terminal areas, where NE storage and extraneuronal metabolism predominates.Young male Sprague-Dawley rats were randomly assigned to three conditions: 1) 24-h access to activity wheel running, 2) treadmill running without electric shock at 0° incline for 1 h·d-1 at 25-30 m·min-1, or 3) a sedentary control group. Treadmill exercise training, but not wheel running, increased the oxidative capacity of soleus muscle indicated by succinate dehydrogenase activity (μmol cytochrome C reduced·min-1·g-1 wet weight).Our results indicated that treadmill exercise training was accompanied by noradrenergic adaptations in the brain consistent with increased metabolism of NE in areas containing NE cell bodies and ascending terminals, whereas treadmill running and wheel running were accompanied by increases in levels of NE in the areas of NE cell bodies and the spinal cord without an exercise training effect (see Tables 1 and 2). Our findings suggested no change or reduction in NE metabolism in the cell bodies and the spinal cord, consistent with tissue-specific decreases in peripheral noradrenergic activity reported after chronic exercise in some studies(38). However, the meaning of the increased NE and DHPG in the pons medulla was unclear since some synthesis and most storage of NE occurs in NE terminals. DHPG is derived from deamination of released NE after reuptake by the NE neuron, thus increased DHPG can indicate increased release of NE in terminal areas (23,47). Increased DHPG in the pons medulla after treadmill training might indicate increased autoinhibitory activity of NE cell bodies (23) which would decrease NE synthesis and the discharge rate of NE neurons.TABLE 1. Norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 3, 4-dihydroxyphenylglycol (DHPG) concentrations in brain frontal cortex and hippocampus for activity wheel running (WR), treadmill running (TR) and control (C) rats.TABLE 2. Norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) concentrations in pons medulla and spinal cord for activity wheel running (WR), treadmill running (TR) and control (C) rats.Our findings extended reports from previous studies of increases in whole brain NE concentrations following treadmill training, forced swimming, and operant wheel running by indicating that NE levels differed according to brain regions. Despite regional differences, we also detected a less pronounced pattern of effects that suggested a general increase in noradrenergic activity. Of the 17 statistically nonsignificant comparisons of conditions for NE, MHPG, and DHPG, 12 revealed higher levels for the running groups compared with controls. The mean effect for these 12 group differences was more than one-half standard deviation, which is moderately large. We avoided the problem of confounding exercise with other noradrenergic stressors, common in previous studies reporting regional differences in NE and MHPG after chronic exercise. Nonetheless, our findings for the treadmill condition were limited to exercise training during the light cycle. A reversed dark-light cycle is better suited to the nocturnal activity patterns of rats than our use of treadmill training during the light cycle and is preferred for future studies.Even when controlling the time of day, it is difficult to compare directly the stress of forced treadmill running with that of voluntary wheel running. Not only do intensity and duration differ between the two modes, but emotional stress likely differs as well. Treadmill running is accompanied by a 50% increase in microneurographic discharge above active waking in LC cell bodies of cats compared with a 600% increase during tail pinch(53). Hence, activity in NE neurons may differ to the extent that locomotion is aversive. We observed that NE levels in the pons medulla and spinal cord were increased similarly after chronic treadmill running and voluntary wheel running, but the increased metabolism in ascending terminals for NE was limited to the treadmill exercise group. Thus it is possible that locomotory influences on NE activity are similar for each mode of exercise but that treadmill training has a specific effect of increasing NE activity in higher brain regions. Future studies using different modes of exercise or comparing responses to them, must address the aversiveness of the physical activity before drawing conclusions about the metabolic influences of exercise on brain NE activity. Nonetheless, our initial study confirmed that chronic physical activity alters brain levels of NE and its major metabolites in regions known to be involved in integrating behavioral and endocrine responses to stressors other than exercise.ANIMAL BEHAVIOR MODELSWe were unaware of studies showing changes in behavior, concomitantly with changes in brain monoamines, after chronic exercise using an established experimental model of depression or anxiety. We began a series of such studies, retaining our focus on brain norepinephrine. There is consensus that the LC-NE system modulates external and internal stimuli to regulate autonomic arousal, attention-vigilance, and neuroendocrine responses involved with behavioral responses to stress (10,23). The LC receives primary afferents from the central nucleus of the amygdala, the CA1 region of the hippocampus (24), and from somatosensory afferents via the paragigantocellular reticular nucleus(23). Activity in the LC is inhibited presynaptically by NE, 5-HT, GABA, and opioid peptides including β-endorphin and metenkephalin (10,23,24).Behavioral models of depression and anxiety developed in the rat commonly use uncontrollable, inescapable conditions such as forced swimming(50) or restraint (26). The escape-deficit model after uncontrollable footshock is the most elaborated model (35,74), first reported by McCulloch and Bruner (39) over 55 years ago. The hallmark response to uncontrollable, inescapable footshock is increased latency to escape from controllable shock administered 24-72 h later(70,71), presumably resulting from depletion of NE in the LC. A single session of high intensity uncontrollable footshock leads to a large decrease in brain NE(5,27,37) with less reliable decreases in levels of brain 5-HT and DA (71), perhaps owing to slower resynthesis of NE (5).In addition to lowered levels of NE in the LC, hippocampus, hypothalamus, and frontal cortex (70), uncontrollable footshock leads to behavior changes in the rat that mimic features of human depression and/or anxiety (74). These are reversed by antidepressant tricyclic drugs such as imipramine and other agonists and antagonists of noradrenergic, dopaminergic, serotonergic and GABAergic receptors(1,37,57). These features of depression include altered sleep, weight loss, anhedonia, and reductions in physical activity, eating, and sex behavior. Also, in major depression and panic disorder, there is an apparent failure in the restraint of the hypothalamic-pituitary-adrenal (HPA) cortical response to stress normally provided by feedback from glucocorticoids to the hypothalamus and the hippocampus and by the brain monoaminergic systems(51).In our first behavioral study (15) we examined the effects of chronic physical activity on brain monoamines and behavior using the escape-deficit model of uncontrollable footshock. We hypothesized that chronic activity wheel running would attenuate the depletion of brain norepinephrine and shorten the latency to escape controllable footshock after exposure to uncontrollable, inescapable footshock delivered the previous day. We used HPLC-EC to measure brain levels of NE, DA, DOPAC, 5-HT and its metabolite, 5-hydroxy indoleacetic acid (5-HIAA) in the LC and its terminal areas in the dorsal raphe, the central amygdala, and area CA1 of the hippocampus. We also assayed the midbrain central gray region, which plays a role in hippocampal-amygdalar models of anxiety (48) and analgesia (17), providing indirect evidence for alternative explanations of escapelatency from footshock. In addition, we assayed prolactin and ACTH in plasma by radioimmunoassay to examine the effects of footshock controllability on HPA responses(36). Activation of the brain noradrenergic and serotonergic systems during stress is believed to increase the secretion of ACTH by stimulating corticotropin releasing factor (CRF) release from the parvocellular area of the paraventricular nucleus (PVN)(4,49), although the effects of NE are controversial (49,64). Inhibition of dopamine activity in the arcuate nucleus permits the release of prolactin(4), while 5-HT and NE can modulate prolactin release via the stimulatory effects of thyrotropin releasing hormone(4). We measured fitness by using an enzymatic assay of the activity of SDH in soleus muscle.Young female Sprague-Dawley rats were randomly assigned to remain sedentary in individual cages or to have 24-h access to activity wheels. After 9-12 wk, animals were matched in pairs according to mass and daily running distance. An animal from each matched pair was randomly assigned to controllable (by learning to press a lever, the animal could end the shock) or uncontrollable, inescapable footshock followed the next day by a footshock escape test in a shuttle box. Testing was counterbalanced in 4-d cycles to control for estrous.Chronic activity wheel running attenuated the escape deficit resulting from uncontrollable footshock (see Fig. 2). The effect was associated with higher levels of NE in the LC (see Fig. 3) and dorsal raphe for activity wheel animals compared with sedentary animals that were footshocked, with higher levels of 5-HT in the central amygdala and higher 5-HIAA in the central amygdala and the CA1 area of the hippocampus for the sedentary, footshocked animals. The activity wheel animals had NE levels that were similar to sedentary animals that did not receive footshock. There were no group differences in monoamines in the central grey or in plasma levels of ACTH and prolactin measured by radioimmunoassay.Figure 2-Latency to escape footshock among rats assigned to controllable or uncontrollable, inescapable footshock on the previous day. Rats with 24-h access to activity wheels for 9-12 wk had shorter escape latency after uncontrollable footshock and when escape latency was averaged across the controllable and uncontrollable footshock conditions,P < 0.02. Values are means ± SEM. Adapted from Dishman, R. K., K. J. Renner, S. D. Youngstedt, et al. Activity wheel running moderates escape latency and brain monoamines after uncontrollable footshock.Brain Res. Bull. (in press).Figure 3-(A) Brain concentrations of norepinephrine (NE), (B) dopamine, (C) DOPAC, and (D) the DOPAC/dopamine ratio in the locus coeruleus after escapable footshock. Rats with 24-h access to activity wheels for 9-12 wk were compared with sedentary rats after conditions of controllable or uncontrollable inescapable footshock on the previous day. NE was lower in sedentary rats compared with activity wheel rats after uncontrollable footshock, P < 0.02, and when NE was averaged across the controllable and uncontrollable footshock conditions,P < 0.001. Values are means ± SEM. Adapted from Dishman, R. K., K. J. Renner, S. D. Youngstedt, et al. Activity wheel running moderates escape latency and brain monoamines after uncontrollable footshock. Brain Res. Bull. (in press).Our results indicated that chronic activity wheel running protects against the depletion of NE induced by uncontrollable footshock in sedentary animals. Since various stressors that deplete NE acutely lead to increased synthesis and storage after chronic exposure (23), it is plausible that activity wheel running also increases synthesis/storage, but we did not measure synthesis or storage directly. Also, we did not use a group that ran in activity wheels but were not footshocked, a comparison group that would have clarified whether the higher NE levels in the activity wheel groups resulted in elevated NE above sedentary controls prior to footshock.The convergence of the behavioral and brain monoamine results provided what I believe was the first psychopharmacological evidence consistent with an antidepressant effect of physical activity. However, wheel running did not result in increased oxidative capacity of locomotory muscle and had no impact on endocrine responses to footshock; these observations indicated that the changes in brain monoamines and behavior did not depend upon a traditionally defined fitness effect of exercise training and did not extend to changes in the HPA axis, which is typically dysregulated in major depression. We replicated the absence of endocrine responses after wheel running in another study using male rats derived from the Fischer strain(16). In that study rats with 24-h access to activity wheels had similar plasma levels of radioimmunoassayed ACTH, corticosterone, and prolactin compared with sedentary animals after uncontrollable footshock(see Fig. 4), despite the fact that the activity wheel group did not have the suppression of Natural Killer (NK) cell activity after footshock common in sedentary animals (16,56) and that has been reported after chronic stress in depressed humans(28).Figure 4-(A) Plasma [adrenocorticotrophin] (pg·ml-1),(B) [corticosterone] (μg·dl-1) and (C) [prolactin](ng·ml-1) after controllable or uncontrollable footshock in male Fischer rats with 24-h access to activity wheels or were sedentary compared with a home-cage control group. No significant main effects or interactions for the training or footshock conditions were found, P≥ 0.10. Values are means ± SEM. Reprinted with permission from Dishman, R. K., J. M. Warren, S. D. Youngstedt, et al. Activity wheel running attenuates suppression of Natural Killer Cell activity after footshock.J. Appl. Physiol. 78:1547-1554, 1995.ENDOCRINE RESPONSESModels of depression and anxiety using the traditions of biological psychology include a central role for the dysregulation of the HPA cortical axis. Therefore, we conducted additional studies on HPA responses to stressors using treadmill exercise training rather than activity wheel running. We thought treadmill training might induce different effects owing to its mode or its forced rather than voluntary features. Since women have a higher prevalence of major depression and panic disorders, we also examined the interaction of the HPA and hypothalamic-pituitary-gonadal (HPG) axes during stress in female rats. Blood levels of ACTH and prolactin in response to stress vary with different stages of the estrous cycle(65). Effects of heavy exercise training on HPA and HPG responses have been described after exercise and rest(7,34,66), but we could not locate studies of HPA-HPG interactions to stressors other than exercise after exercise training.In the first experiment (72), we used ovariectomized female rats with estradiol replacement to examine the moderating effect of the HPG axis on HPA hormonal responses to stress. Ovariectomized female Sprague Dawley rats that had been treadmill exercise trained or sedentary for 6 wk received intramuscular injections of estradiol benzoate or sesame oil vehicle on each of 3 d prior to 15 min of acute treadmill running or immobilization(i.e., a passive stressor). Plasma ACTH, corticosterone, and prolactin concentrations were determined from trunk blood by radioimmunoassay. Home-cage sedentary animals provided baseline hormone levels in the absence of a stressor. ACTH and corticosterone levels were elevated after acute sessions of immobilization or treadmill running in animals treated with either estradiol or oil vehicle compared to home-cage animals, but increases in prolactin after stressors were dependent on estradiol. Treadmill exercise training increased the oxidative capacity (SDH activity) of soleus muscle and led to an attenuation of ACTH and prolactin to running when compared with sedentary animals. In contrast, treadmill exercise training led to elevated levels of ACTH after novel immobilization with no effect on prolactin levels (seeFig. 5).Figure 5-Plasma adrenocorticotropin (ACTH) levels(pg·ml-1) in the treadmill trained and sedentary experimental groups following running or immobilization and home-cage control groups. A significant main effect for treatment condition (estradiol vs oil) and a significant training group (treadmill trained vs sedentary)-by-stressor (acute running vs immobilization) interaction are depicted. ACTH levels were elevated after immobilization stress in the treadmill trained group compared with sedentary controls. Values are means ± SEM. P≤ 0.01. Reprinted with permission from White-Welkley, J. E., B. N. Bunnell, E. H. Mougey, J. L. Meyerhoff, and R. K. Dishman. Treadmill exercise training and estradiol differentially modulate hypothalamicpituitary-adrenal cortical responses to acute running and immobilization. Physiol. Behav. 57:533-540, 1995.We observed similar results in a second study (73) that replicated the methods of the aforementioned study with the following changes: estriadiol was replaced during the exercise training period, and venous levels of plasma ACTH and prolactin were sampled for 30 min after footshock. Again, treadmill exercise training that increased SDH activity in soleus locomotory muscle resulted in elevated levels of ACTH and prolactin in plasma after novel footshock among animals treated with estradiol when compared with sedentary controls.The effects of the estradiol treatment in both studies were consistent with an interaction of the HPA and HPG axes in response to stress. Whether such an interaction and the elevated levels of ACTH after nonexercise stressors that we observed after treadmill exercise training have positive or negative consequences for depression, anxiety, or physical performance requires study. Also, the mechanisms for the increased ACTH response, other than reduced clearance, after treadmill exercise training are not known. During high intensity exercise, ACTH levels are elevated among highly trained males(46) and increase despite infusion of CRF sufficient to saturate pituitary corticotrophs (58). Thus, releasing factors other than CRF, including arginine vasopressin (AVP)(25), may influence ACTH levels during intense exercise(29,46). It is not known whether exercise training alters noradrenergic, serotonergic, or dopaminergic activity in hypothalamic and suprahypothalamic regions that modulate pituitary responses to stress.VALIDITY OF ANIMAL MODELSCaution is needed when conferring human moods and emotions upon animal behaviors during stressor tasks. The labeling and interpretation of poorly defined emotional states... “may be more in the eye of the beholder than in the brain of the animal” (31), explaining why the same task administered in different laboratories sometimes is interpreted differently.A taxonomy commonly used in pharmacology(31,74), judging whether animal models that use stressor tasks are predictive, isomorphic, or homologous, is helpful in comparing their validity for human depression and anxiety. Predictive models include specific signs or behaviors that can be reliably changed by drugs known to have clinical efficacy in humans. If footshock has predictive validity for human disorders, drugs that are clinically effective for reducing depression or anxiety in humans should reduce escape latency. Predictive models must be based on species or strains that respond to drugs in the same ways as humans do. An isomorphic model evokes the same features of the human disease, which abate after administering drugs that are clinically useful in humans, but the features generated may not have the same etiology, i.e., course of development, as in the human disease. A homologous model meets the standards of predictive validity and isomorphism, and it also has the same etiology as does the human disease. When a homologous model is specific for a single disease, it has construct validity, which is the gold standard or the ideal test of validity.The aforementioned escape-deficit model is an attempt to simulate the so-called “learned helplessness”(35,71) or behavioral despair(50) common in human depression. The animal gives up in its attempts to escape stressors such as footshock, forced swimming, or restraint. The escape-deficit model is mostly isomorphic with human depression, featuring weight loss, reduced sex behavior, sleep disturbances(decreased rapid eye movement (REM) sleep latency), and anhedonia, i.e., loss of pleasure. However, such a model is not homologous with human depression. Although self-reward tasks such as sucrose preference and intracranial self-stimulation are used as surrogate measures in the rat for the phenomenological construct of pleasure experienced by humans, it is not possible to determine if a rodent feels helpless or hopeless. Also, certain types of depression and anxiety in humans appear to be endogenous, and they cannot be attributed to an uncontrollable stressor. A relatively new model of endogenous depression in the rat involves injecting neonatal pups with clomipramine (CLI), a 5-HT reuptake inhibitor, leading to decreased REM sleep latency and other key behavioral signs of depression upon reaching adulthood(67). This model is isomorphic with human depression, and it is responsive to pharmacotherapy. Since its endogenous etiology differs from other animal models based on exogenous stress, the CLI model has potential for studying the role of physical activity in preventing depression not arising from chronic stress (75,76).Depression. Although the escape-deficit model and the neonatal-CLI model are largely isomorphic with shared features of human depression, their construct validity for depression remains unclear since most of the features they induce also are common to anxiety disorders. Early findings of reversibility of some features by tricyclics, but not by anxiolytic drugs (57), supported the predictive validity uncontrollable footshock as a model of depression. Subsequent reports comparing anxiolytics and atypical antidepressants have not resolved whether the predictive validity of the escape-deficit model is specific for depression more so than for anxiety. Behavioral responses similar to those induced by inescapable footshock are seen after injection of the inverse benzodiazepine agonist β-carboline, which induces anxiety (18), or the administration of diazepam, which reduces anxiety, to rats prior to inescapable shock attenuates the escape-deficit 24 h later(19).Notwithstanding views that anxiety and depression exist along a continuum with a common etiology, there is no scientific consensus as to whether the increased latency to escape shock represents depression, indicated by learned helplessness or behavioral despair, more than it represents anxiety. Other plausible explanations for escape latency include interference with learning, analgesia, or a motor deficit. Hence, using an established model of anxiety behavior in the rat (40), we examined whether chronic physical activity affects mesolimbic-motor integrations.Anxiety. Increased locomotion usually reflects an adaptive motivational state indicating reduced behavioral inhibition (e.g., less freezing) (55). An increase in open field locomotion has been reported in rats following forced exercise swimming(62) and after motorized treadmill running(62,69). We (13) and others(43) have shown that locomotion by the rat in an open field is associated inversely with observer ratings of anxiety when the locomotion appears purposeful and the animal exhibits other exploratory behaviors such as rearing or approaching the center of the open field. In contrast, low levels of locomotion, few approaches to the center of the open field, freezing, defecation, urination, and shivering are conventionally regarded as isomorphic with the hypervigilance, hesitancy, fear, and autonomic activation common in human anxiety (45). Under certain circumstances of threat, increased locomotion seems to indicate panic (i.e., the flight response to a predator) (40,48). Such a dichotomous interpretation of increased locomotion during open-field testing illustrates the importance of environmental context when inferring anxiety from locomotion by rats (8,13,43).Neurobiological mechanisms for the presumed anxiolytic effects of exercise have not been advanced using an established animal model of anxiety. The limbic-motor integration model of anxiety elaborated by Mogenson(40) is relevant for the study of physical activity and anxiety behaviors in the rat. In this model fearful locomotion is controlled by the limbic system's modulation of the segmental pedunculopontine nucleus of the mesencephalic locomotor system by reciprocal inhibition between GABA and dopamine transmission within the corpus striatum. GABA efferents from the nucleus accumbens to the ventral pallidum apparently inhibit locomotion.We were unaware of studies that examined striatal GABA concentrations or GABAA receptors (specific for the antianxiety benzodiazepines) concomitantly with open-field behavior after manipulating physical activity in the rat. Hence we (14) tested the hypothesis that chronic physical activity would increase locomotion during open-field behavior testing and decrease the density of GABAA receptors in the corpus striatum consequent to increased GABA concentration.Young male Sprague-Dawley rats were randomly assigned to three conditions: 24-h access to an activity wheel, running for 1 h without shock 6 d·wk-1 on a motorized treadmill, or sedentary control. After 8 wk, open-field locomotion increased only in the activity wheel group. GABAA receptor density, indicated by 3H-bicuculline binding(fmol·mg-1), was lower for activity wheel animals compared with treadmill animals and controls. GABA concentration(μmol·g-1), determined by HPLC-EC was elevated in the activity wheel and treadmill groups. Our finding of increased open-field locomotion after wheel running (see Fig. 6), concomitant with decreased GABAA receptor density (see Fig. 7) in the corpus striatum, supported the concept that chronic wheel running has an anxiolytic effect, as defined by the limbicmotor integration model of anxiety related behavior (40).Figure 6-(A) Open-field locomotion (total squares) increased for young male rats with 24-h access to activity wheels for 8 wk, decreased for rats that were treadmill exercise trained, and did not change for sedentary controls (P = 0.01). (B) A similar pattern of across the groups was observed for locomotion toward the center of the open field(P < 0.05), and (C) experimenter ratings of anxiety related behavior. Values are means ± SEM for N = 8. Reprinted with permission from Dishman, R. K., A. Dunn, S. Youngstedt, et al. Increased open-field locomotion and decreased striatal GABAA binding after activity wheel running. Physiol. Behav. 60:699-705, 1996.Figure 7-(A) 3H-bicuculline methyl chloride binding in the corpus striatum was decreased in young male rats with 24-h access to activity wheels for 8 wk compared with treadmill trained rats and sedentary controls(P < 0.05). (B) GABA levels in the corpus striatum were higher for the activity wheel and treadmill rats compared with sedentary controls (P < 0.01). Values are means ± SEM for N = 8. Reprinted with permission from Dishman, R. K., A. Dunn, S. Youngstedt, et al. Increased open-field locomotion and decreased striatal GABAA binding after activity wheel running.Physiol. Behav. 60:699-705, 1996.SUMMARYChronic exposure to nonexercise stressors leads to enhanced presynaptic activity in NE neurons accompanied by a compensatory increase in NE storage(23). Also, increased activity by tyrosine hydroxylase has been observed in LC-NE terminal areas in hippocampus and frontal cortex, indicative of increased synthesis of dopamine and NE. It is plausible that acute episodes of voluntary or forced exercise could lead to increased metabolism and synthesis of monoamines in a way similar to other chronic stressors, leading to an inoculation against brain depletion of monoamines, dysregulation of pituitary-adrenal cortical responses, and/or maladaptive behavioral responses to uncontrollable, unpredictable nonexercise stressors(20). Earlier studies reported that acute forced exercise depleted brain NE (3,60) and decreased the metabolism of 5-HT (9), whereas our research shows that chronic activity wheel running and treadmill exercise training increase NE or its metabolites (21) in the pons medulla, frontal cortex, and hippocampus, brain areas that are activated during integrated behavioral responses to stressors that evoke anxiety and depression. In addition, our results show that chronic activity wheel running protects against depletion of brain NE levels in response to footshock. The changes we observed in NE levels and GABAA receptor density after wheel running were associated with behavioral adaptations that imply antidepressant and anxiolytic effects of voluntary physical activity. Their significance for adaptations by the HPA axis after footshock is not clear since plasma levels of ACTH, corticosterone, and prolactin were not affected by activity wheel running. In contrast, treadmill exercise training increased ACTH responses to footshock and immobilization. Hence, studies are needed to determine the role of brain monoamines in regulating the HPA axis after treadmill exercise.It is important to determine whether a therapeutic dose of physical activity for antidepressant and antianxiety effects exists. With the exception that treadmill exercise training increased ACTH after immobilization and footshock, our findings were not dependent on an exercise training effect defined as increased oxidative capacity of locomotory muscle. However, reductions in depression and anxiety among humans could depend upon increased neuromuscular strength or endurance, perhaps mediated by increased self esteem, or as our present findings suggest, adaptations by brain monoaminergic systems with implications for resisting neural fatigue during stress. Moreover, our findings, when strictly interpreted, show salutary effects of normal circadian physical activity only when contrasted with the forced inactivity that typifies animal husbandry. Hence, a classic dose-response gradient of lowered depression or anxiety with increasing physical activity remains to be demonstrated. Also, the comparative effects of forced exercise versus voluntary physical activity requires more study.Finally, the psychopharmacologic methods we have used are descriptive, limiting conclusions about brain neural activity. Levels of DHPG, MHPG, DOPAC, and 5-HIAA are conventionally used as estimates of monoamine metabolism and neural activity. However, direct measures of the release, synthesis, and turnover of NE, dopamine, and 5-HT are needed to determine the metabolic activity in monoamine neurons during and after physical activity. Nonetheless, our results suggest target areas in the brain and spinal cord for studies using more direct measures of NE release during acute running or other stressors (e.g., using microdialysis). One report (47) using microdialysis indicated increased release of NE, followed by increased MHPG and DHPG, in the frontal cortex after acute treadmill running. Measuring the activity of rate-limiting enzymes such as tyrosine hydroxylase, e.g., messenger RNA activity, in brain regions can clarify the meaning of the changes in levels of NE and its metabolites. Changes in pre- and post-synaptic adrenoreceptor-effector systems may also be informative. 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and Arthroscopy Review200210110-14MAR 2002Endocrinologic Changes in Exercising WomenArena, B; Maffulli, N