Adrenergic and Dopaminergic Response to Chronic Chair Restraint in the Rhesus Monkey

MARK J. PERLOW, MD, FAROUK KAROUM, PHD, DELORES BRAUN, AND RICHARD JED WYATT, MD Prolonged chair restraint and social isolation in the rhesus monkey led to a reduction in the urinary excretion of HVA (4-hydrdxy-3-methoxyphenylacetic acid), DOPAC (3,4dihydroxyphenylacetic acid), VMA (3-methoxy-4-hydroxymandelic acid), and MHPG (3methoxy-4-hydroxyphenylethylglycol) over a 3 week period. This adaptation to a chronically "stressful" situation corresponds to earlier studies on the rhesus monkey indicating a gradual reduction in the urinary excretion of norepinephrine and epinephrine after initiation of restraint. The following basic information on the urinary excretion of catecholamine metabolites was obtained: (1) the rate of excretion of the dopamine metabolites (HVA and DOPAC) is about four times higher than the rate of excretion of adrenergic metabolites (VMA and MHPG); (2) MHPG is the major adrenergic metabolite in the rhesus monkey; and (3) the excretion rates of the urinary metabolites varied considerably between animals.

INTRODUCTION

Over 60 years ago, W.B. Cannon demonstrated that emotional stimuli could cause the adrenal gland to secrete catecholamines (1). Since then, there have been numerous studies investigating the effects of various psychological stimuli on pituitary-adrenocortical and sympathetic-adrenal medullary activity. Only a small number of these studies have investigated the biologic response of animals to chronic situational changes (2, 3), and few deal with primates. With this as background, we decided to investigate the response of monkeys to long-term chair restraint and social isola-

tion. These environmental changes were felt to have a primary, although not exclusively, psychological effect upon the animal. By studying the monkey in this paradigm, we have been able to demonstrate changes in the excretion of catecholamine metabolites at various stages in the adaptation to a novel and stressful situation.
METHODS

Male rhesus monkeys [Macaca mulatto), weighing 5.1 7.0 kg, were studied. They were housed in individual cages for at least 23 months before chair restraint. The animals were anesthetized with ketamine hydrochloride (50 mg, I.M.) (Parke, Davis, Detroit, Mich.), and placed in a primate restraining chair. After recovery from the effects of the anestheFrom the Laboratory of Clinical Psychophar- tic (0.5 1 hour), the chair and monkey were placed macology, Division of Special Mental Health Re- in a well-ventilated, sound-attenuated chamber with search, Intramural Research Program, National Insti- 12 hours of fluorescent light (6:00 A.M.-6:00 P.M.) tute of Mental Health, St. Elizabeth's Hospital, Wash- and 12 hours of darkness (6:00 P.M.-6:00 A.M.). A ington, D.C. 20032. standard primate diet of food pellets (Purina Monkey Address reprint requests to: Mark J. Perlow, M.D., Chow) and apples was dispensed each morning Laboratory of Clinical Psychopharmacology, Wil- (8:00-10:00 A.M.), and the aimals fed themselves. liam A. White Building, Room 536, St. Elizabeth's Water was allowed ad lib. up to 800 ml/day (4, 5). Hospital, Washington, D.C. 20032. Received for publication May 10, 1978, final revi- Each chamber was fitted with a giant funnel to collect urine. As the urine was excreted, it was sepasion received November 28, 1978. Psychosomatic Medicine Vol. 4 1 , No. 2 (March 1979)
Copyright " 1979 by the American Psychosomal Published by Elsevier North Holland, Inc.

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M. J. PERLOW ET AL. rated from the feces by a gauze filter, collected in plastic bottles (Nagle, Rochester, N. Y.), and immediately frozen at -40C. 24-hour urines were subsequently stored at -10C for 3 months. The first day of urine collection began approximately 24 hours after the ketamine anesthesia and initiation of chair restraint. For biochemical analysis, three consecutive 24-hour samples were defrosted and mixed together with 15 ml of 10% disodium ethylenediamine tetraacetate. An aliquot of this mixture was refrozeri (-80C) and assayed 1-2 months later for total 3-methoxy-4-hydroxyphenylethylglycol (MHPG), and free 3-methoxy-4-hydroxymandelic acid (VMA), 4-hydroxy-3-methoxyphenylacetic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) using gas chromatographic mass spectroscopic methodology (6). In these analyses deuterated MHPG PH3-MHPG), DOPAC PHs-DOPAC), HVA (2H3-HVA), and VMA (2Hs-VMA) were used as internal reference standards. 25 mg of each of these reference standards was added to each sample at the beginning of the assay. To quantify the amount of the free acid metabolites present in the samples, free VMA, DOPAC, and HVA (25, 50, and 100 mg) were added to one urine sample in triplicate at the beginning of the analysis. From the difference between the amount of substance present in the urine with and without these latter standards, calibration curves were constructed and used to quantify the amount of free acids present in each urine sample. The methyl ester pentafluoropropionyl derivatives of the acid metabolites were prepared and analyzed (6). For the quantification of total MHPG, the sulfate and glucuronide conjugates of MHPG were first hydrolyzed with a crude sulfatase preparation (Sigma Chemical Co., St. Louis, Mo.) as previously reported (6). After hydrolysis, MHPG was extracted into ethyl acetate and measured essentially as described for the acid metabolites. The pentafluoropropionyl derivative was prepared for MHPG analysis. Separation of the different metabolites was achieved on an 8-ft 1-in i.d. steel column packed with 3% SE 54 coated on 80/100 mesh chromosorb G (Pierce Chemical Co., Rockford 111.). A Finnigan model 3200 quadrupole gas chromatograph mass spectrometer was used. The fragments employed for mass fragmentography were as previously reported (6).

period immediately after initiation of chair restraint is presented in Table 1. Even after correction for body weight differences, there is considerable inter-monkey variation in the rate of excretion of all four metabolites. For individual monkeys, the magnitude of the variation in excretion rates between the highest and lowest rates for HVA, DOPAC, MHPG, and VMA is 2.7, 9.5, 1.7, and 2.9, respectively. Although there is no consistent correlation relationship between the excretion rates of each of the metabolites for individual animals, the individual rate of excretion of the dopamine metabolites, HVA and DOPAC, is greater than the excretion of the norepinephrine and epinephrine metabolites, VMA and MHPG, and the excretion of MHPG is greater than the excretion of VMA. Using a repeated measure analysis of variance for a single factor, we are able to demonstrate a reduction in the excretion of MHPG (F = 4.16, p = 0.030), VMA (F = 2.03, p = 0.162), HVA (F = 3.60, p = 0.046), and DOPAC (F = 3.67, p = 0.056) over the experimental period. By days 1921, the respective excretion rates of MHPG, VMA, HVA, and DOPAC were 68.7, 76.4, 67.5, and 77.2% of the rates observed on days 2-4. A Newman-Keuls test demonstrated a significant fp < 0.05) difference in the rates of excretion of

TABLE 1. Urinary Excretion of Catecholamine Metabolites in Monkeys Immediately After Chair

Restraint (/xg/kg/24 hr) Monkey Weight (kg) HVA 707 508 706 854 842 5.1 5.6 5.2 6.0 7.0 835 419 327 480 380 DOPAC 193 146 93 881 563 MHPG VMA 123 80 104 135 117 96 24 70 44 33

RESULTS

The pattern of urinary excretion of catecholamine metabolites in the 3-day

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MHPG, HVA, and DOPAC between days 2-4 and days 19-21. Body locomotor activity, although not specifically monitored, appeared to be unchanged during the experimental period. Dietary intake was measured daily and was constant during the experimental period, and for the 1-month period after this investigation, during which the animal remained restrained.
DISCUSSION

Various naturally occurring and experimental paradigms have been used to study the catecholamine response to life situations, especially those considered to be stressful (2, 3). A great many experiments have used rodents and subjected them to stress in the form of muscle exhaustion, environmental temperature extremes, limb ischemia, electric shock, shaking, paradoxical sleep deprivation, swimming, hemorrhage, and immobilization (7-33). Although the actual concen-

O Uj \ ^ A A

MHPG VMA HVA OOPAC

I
Z80

10

15

20

25

DAYS

Fig. 1. Urinary excretion of catecholamine metabolites in monkeys after chair restraint. Values for each metabolite is expressed as percent of quantity of metabolite excreted on days 2-4.

tration of catecholamines in brain tissue did not consistently increase or decrease, the authors generally agreed that norepinephrine turnover in the brain was increased during acutely stressful situations. In situations where brain tissue could not be examined, as with most human studies, catecholamine studies have relied upon biochemical analyses of urine and blood. Most authors would agree that concentration changes of plasma and urinary catecholamines and catecholamine metabolites reflect alterations in the turnover rate of catecholamines. With stresses of various types the concentration of norepinephrine and epinephrine increase (2, 34-46). Representing only 0.5-6.0% of that released from synaptic nerve endings (40, 47-49), a fluctuation in the urine concentration of norepinephrine and epinephrine corresponds to similar changes in the concentration of urinary VMA (42, 47). For the 3-day period after initiation of chair restraint, monkeys excreted approximately 8 /u.g of epinephrine and norepinephrine per day (46, 50). In the experiment presented here, in similarly prepared animals, the monkeys excreted 946 fxg (range 581-1,120 /Ag) of VMA and MHPG per day. Chair restraint produced a threefold increase in urinary epinephrine and a twofold increase in urinary norepinephrine (46,50). The urinary excretion rates for these compounds returned to stable base-line levels after 1 week. The patterns of urinary norepinephrine and epinephrine excretion do not correspond to the more gradual reduction in the excretion of MHPG or VMA. Urine MHPG and VMA excretion rates declined 31.3 and 23.6%, respectively, over a 21-day period. The cause for this difference in excretion is unknown but merits further study.
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The decline in norepinephrine metabolism may be the result of adaptation to the physical restraint itself, or, as a result of prolonged social isolation and reduction of stimulation from environment. Social isolation results in behavioral abnormalities in monkeys (51) and, in rodents, is associated with a decrease in brain dopamine and norepinephrine turnover, and a reduction in adrenal catecholamine-synthesizing enzymes (53-57). "Stress" in rodents has been shown to alter the concentration and the turnover of dopamine in brain tissue (7-11, 13, 14, 18, 20, 22, 52, 58-61). Unlike norepinephrine, where there is a general agreement that "stress" increases norepinephrine turnover, there is no concensus of opinion as to whether dopamine turnover increases, decreases, or remains unchanged in response to stress. This variation may reflect variations in the strain of animal studied, the stressor used, the intensity and duration of the stressor and the portion of the brain studied. As the monkeys adapted to the novel environment, they excreted smaller amounts of DOPAC and HVA, suggesting that over the 3-week study period there was a reduction in dopamine turnover. Because we are unable to determine if the metabolities come from the central or the peripheral nervous system, we are unable to determine if dopamine turnover in the brain decreased during chair adaptation. When normal volunteers or individuals with psychiatric illnesses were exposed to different environmental situations, they excreted varying amounts of norepinephrine and epinephrine (2, 34, 35, 37-41, 43, 48, 61). Analyses of these results have led investigators to hypothesize that: (1) the concentrations and the ratio of urinary epinephrine/norepinephrine response in an individual's behavioral state and the
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manner in which he will respond to the inducing stimulus, and (2) the norepinephrine and epinephrine response is a reflection of this general response to the inducing stimulus. We had hoped that our experiment would extend the observations that serve as bases for these hypotheses (46,50). As a result of previous studies in which norepinephrine were measured (46,50), we felt that the amount of urinary adrenergic metabolites would increase with chair restraint. As urinary VMA is considered to have its origin in pools of catecholamines outside the brain and urinary MHPG to have its origin in pools of norepinephrine in both the body and the brain (62), we postulated that their differential increase would reflect the peripheral and central adrenergic response to the stressor. We also hoped that as the animals adapted to the chair restraint and social isolation, and the amounts of catecholamine metabolites decreased, the ratio of VMA/MHPG would change reflecting perhaps, a change in excretion patterns of epinephrine and norepinephrine, an alteration in metabolic pathway for the metabolism of epinephrine and/or norepinephrine, or a differential rate of adaptation of the central vs. peripheral nervous systems to the stressor. Since the rate of decline of urinary excretion of MHPG and VMA was similar, we were unable to speculate upon the above propositions. Despite a similarity of sexual gender, age, and body weight, there was considerable variation between animals in excretion of catecholamine metabolites. A similar variation was noted in earlier studies measuring the excretion of catecholamines and catecholamine metabolites (2, 33-37, 40, 41, 45, 48, 61, 63-66). On a kilogram basis, the variation between highest and lowest excretion rates for

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HVA, DOPAC, MHPG, and VMA is 2.7,9.5,1.7, and 2.9, respectively. Although the ratio of MHPG/VMA is always > 1, the ratio of HVA/DOPAC varies between 0.54 and 4.3. The relative excretion rate of metabolites between animals and the ratio of adrenergic and dopaminergic metabolites in the urine was unchanged after 3 months of chair restraint (unpublished data). From these results we conclude that the excretion of adrenergic metabolites and

dopaminergic metabolites decreases over several weeks after initiation of chronic chair restraint. Despite a considerable variation in base-line excretion rates, the rate of decline of all metabolites is the same, We note the possible usefulness in using metabolites of catecholamines to follow the biochemical response to a "stressor." The authors wish to thank M. Strotkamp and M. Adams for their assistance in the preparation of this paper.

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