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 2—3 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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1. For biochemical analysis. p = 0. 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. Using a repeated measure analysis of variance for a single factor. 24-hour urines were subsequently stored at -10°C for 3 months. and free 3-methoxy-4-hydroxymandelic acid (VMA). Rockford 111.16..M. For individual monkeys. and 2. p = 0. 67. 50. rated from the feces by a gauze filter.030). MHPG was extracted into ethyl acetate and measured essentially as described for the acid metabolites.4-dihydroxyphenylacetic acid (DOPAC) using gas chromatographic mass spectroscopic methodology (6).1 5.9.. DOPAC PHs-DOPAC).2% of the rates observed on days 2-4.7.2 6. is greater than the excretion of the norepinephrine and epinephrine metabolites. 9.0 7. and immediately frozen at -40°C. and 100 mg) were added to one urine sample in triplicate at the beginning of the analysis. The fragments employed for mass fragmentography were as previously reported (6). and DOPAC (F = 3. the respective excretion rates of MHPG. VMA (F = 2. 4-hydroxy-3-methoxyphenylacetic acid (HVA).7. 76. Although there is no consistent correlation relationship between the excretion rates of each of the metabolites for individual animals. The pentafluoropropionyl derivative was prepared for MHPG analysis.5. Y. VMA. MHPG. Even after correction for body weight differences. respectively.7. the sulfate and glucuronide conjugates of MHPG were first hydrolyzed with a crude sulfatase preparation (Sigma Chemical Co. HVA and DOPAC.d. Louis.5. An aliquot of this mixture was refrozeri (-80°C) and assayed 1-2 months later for total 3-methoxy-4-hydroxyphenylethylglycol (MHPG).) as previously reported (6).4. we are able to demonstrate a reduction in the excretion of MHPG (F = 4. free VMA. St.). HVA (2H3-HVA).6 5. A Newman-Keuls test demonstrated a significant fp < 0. Rochester.046). and 77. and DOPAC were 68.03. steel column packed with 3% SE 54 coated on 80/100 mesh chromosorb G (Pierce Chemical Co. The methyl ester pentafluoropropionyl derivatives of the acid metabolites were prepared and analyzed (6). three consecutive 24-hour samples were defrosted and mixed together with 15 ml of 10% disodium ethylenediamine tetraacetate. the individual rate of excretion of the dopamine metabolites.056) over the experimental period. and 3. By days 19—21.67. A Finnigan model 3200 quadrupole gas chromatograph mass spectrometer was used. calibration curves were constructed and used to quantify the amount of free acids present in each urine sample. J. Mo. DOPAC. After hydrolysis. p = 0. HVA (F = 3. The first day of urine collection began approximately 24 hours after the ketamine anesthesia and initiation of chair restraint. p = 0.60.0 835 419 327 480 380 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 140 Psychosomatic Medicine Vol. period immediately after initiation of chair restraint is presented in Table 1. there is considerable inter-monkey variation in the rate of excretion of all four metabolites. the magnitude of the variation in excretion rates between the highest and lowest rates for HVA. 25 mg of each of these reference standards was added to each sample at the beginning of the assay. PERLOW ET AL. No. and VMA (2Hs-VMA) were used as internal reference standards. and VMA is 2. In these analyses deuterated MHPG PH3-MHPG). and the excretion of MHPG is greater than the excretion of VMA. N. DOPAC. Separation of the different metabolites was achieved on an 8-ft 1-in i. 2 (March 1979) .).05) difference in the rates of excretion of TABLE 1. collected in plastic bottles (Nagle. VMA and MHPG. 4 1 . HVA. and HVA (25. From the difference between the amount of substance present in the urine with and without these latter standards.162). To quantify the amount of the free acid metabolites present in the samples. For the quantification of total MHPG.

Most authors would agree that concentration changes of plasma and urinary catecholamines and catecholamine metabolites reflect alterations in the turnover rate of catecholamines. over a 21-day period. DISCUSSION Various naturally occurring and experimental paradigms have been used to study the catecholamine response to life situations. appeared to be unchanged during the experimental period.120 /Ag) of VMA and MHPG per day. as with most human studies. monkeys excreted approximately 8 /u.6%. 50). paradoxical sleep deprivation. the authors generally agreed that norepinephrine turnover in the brain was increased during acutely stressful situations. The patterns of urinary norepinephrine and epinephrine excretion do not correspond to the more gradual reduction in the excretion of MHPG or VMA. A great many experiments have used rodents and subjected them to stress in the form of muscle exhaustion. Urine MHPG and VMA excretion rates declined 31. In situations where brain tissue could not be examined. Dietary intake was measured daily and was constant during the experimental period. hemorrhage. Values for each metabolite is expressed as percent of quantity of metabolite excreted on days 2-4. 3).50). and for the 1-month period after this investigation. Urinary excretion of catecholamine metabolites in monkeys after chair restraint. For the 3-day period after initiation of chair restraint. 47). Chair restraint produced a threefold increase in urinary epinephrine and a twofold increase in urinary norepinephrine (46. Body locomotor activity.3 and 23. tration of catecholamines in brain tissue did not consistently increase or decrease. during which the animal remained restrained. although not specifically monitored.5-6. limb ischemia.CATECHOLAMINERCIC RESPONSE TO STRESS MHPG. especially those considered to be stressful (2. Although the actual concen- • O Uj \ ^ A A MHPG VMA HVA OOPAC I Z80 0 5 10 15 20 25 DAYS Fig. 141 Psychosomatic Medicine Vol. The cause for this difference in excretion is unknown but merits further study. catecholamine studies have relied upon biochemical analyses of urine and blood. and DOPAC between days 2-4 and days 19-21. 1. and immobilization (7-33). Representing only 0. shaking. In the experiment presented here. environmental temperature extremes.g of epinephrine and norepinephrine per day (46. a fluctuation in the urine concentration of norepinephrine and epinephrine corresponds to similar changes in the concentration of urinary VMA (42. No. 4 1 . 47-49). in similarly prepared animals. The urinary excretion rates for these compounds returned to stable base-line levels after 1 week. respectively. 34-46). With stresses of various types the concentration of norepinephrine and epinephrine increase (2. swimming. the monkeys excreted 946 fxg (range 581-1. HVA.0% of that released from synaptic nerve endings (40. electric shock. 2 (March 1979) .

61. Social isolation results in behavioral abnormalities in monkeys (51) and. 61). and (2) the norepinephrine and epinephrine response is a reflection of this general response to the inducing stimulus. On a kilogram basis. where there is a general agreement that "stress" increases norepinephrine turnover. the ratio of VMA/MHPG would change reflecting perhaps. 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). 37-41. We had hoped that our experiment would extend the observations that serve as bases for these hypotheses (46. 45. age. there is no concensus of opinion as to whether dopamine turnover increases. we postulated that their differential increase would reflect the peripheral and central adrenergic response to the stressor. there was considerable variation between animals in excretion of catecholamine metabolites. 52. When normal volunteers or individuals with psychiatric illnesses were exposed to different environmental situations. or. 20. 22. 41. 2 (March 1979) . 63-66).M. 41.50). As the monkeys adapted to the novel environment. Unlike norepinephrine. Because we are unable to determine if the metabolities come from the central or the peripheral nervous system. 13. PERLOW ET AL. 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 142 manner in which he will respond to the inducing stimulus. "Stress" in rodents has been shown to alter the concentration and the turnover of dopamine in brain tissue (7-11. suggesting that over the 3-week study period there was a reduction in dopamine turnover. The decline in norepinephrine metabolism may be the result of adaptation to the physical restraint itself. a change in excretion patterns of epinephrine and norepinephrine. as a result of prolonged social isolation and reduction of stimulation from environment. This variation may reflect variations in the strain of animal studied. As a result of previous studies in which norepinephrine were measured (46. the stressor used. is associated with a decrease in brain dopamine and norepinephrine turnover. Despite a similarity of sexual gender. 14. and body weight.50). we are unable to determine if dopamine turnover in the brain decreased during chair adaptation. 35. A similar variation was noted in earlier studies measuring the excretion of catecholamines and catecholamine metabolites (2. 33-37. and a reduction in adrenal catecholamine-synthesizing enzymes (53-57). We also hoped that as the animals adapted to the chair restraint and social isolation. J. the variation between highest and lowest excretion rates for Psychosomatic Medicine Vol. decreases. Since the rate of decline of urinary excretion of MHPG and VMA was similar. 48. an alteration in metabolic pathway for the metabolism of epinephrine and/or norepinephrine. in rodents. they excreted smaller amounts of DOPAC and HVA. and the amounts of catecholamine metabolites decreased. we felt that the amount of urinary adrenergic metabolites would increase with chair restraint. they excreted varying amounts of norepinephrine and epinephrine (2. 40. or a differential rate of adaptation of the central vs. or remains unchanged in response to stress. 43. 48. peripheral nervous systems to the stressor. 18. No. 34. the intensity and duration of the stressor and the portion of the brain studied. 58-61). we were unable to speculate upon the above propositions.

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