Chair Restraint in Monkey
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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 (3,4-
dihydroxyphenylacetic acid), VMA (3-methoxy-4-hydroxymandelic acid), and MHPG (3-
methoxy-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 re-
straint.
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 dem-onstrated that emotional stimuli could
cause the adrenal gland to secretecatecholamines (1). Since then, there havebeen numerous studies investigating theeffects of various psychological stimuli onpituitary-adrenocortical and sympa-
thetic-adrenal medullary activity. Only asmall number of these studies have inves-tigated the biologic response of animals tochronic situational changes (2, 3), and few
deal with primates.
With this as background, we decided toinvestigate the response of monkeys tolong-term chair restraint and social isola-
From the Laboratory of Clinical Psychophar-macology, Division of Special Mental Health Re-search, Intramural Research Program, National Insti-tute of Mental Health, St. Elizabeth's Hospital, Wash-ington, D.C. 20032.
Address reprint requests to: Mark J. Perlow, M.D.,Laboratory of Clinical Psychopharmacology, Wil-liam A. White Building, Room 536, St. Elizabeth'sHospital, Washington, D.C. 20032.
Received for publication May 10, 1978, final revi-sion received November 28, 1978.
tion. These environmental changes were
felt to have a primary, although not exclu-sively, psychological effect upon the ani-mal. By studying the monkey in this
paradigm, we have been able to demon-strate changes in the excretion ofcatecholamine metabolites at variousstages in the adaptation to a novel andstressful situation.
METHODS
Male rhesus monkeys [Macaca mulatto), weighing
5.1 — 7.0 kg, were studied. They were housed in indi-
vidual 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 restrainingchair. After recovery from the effects of the anesthe-
tic (0.5 — 1 hour), the chair and monkey were placed
in a well-ventilated, sound-attenuated chamber with
12 hours of fluorescent light (6:00 A.M .-6:00 P.M.)and 12 hours of darkness (6:00 P.M.-6:00 A.M.). A
standard primate diet of food pellets (Purina Monkey
Chow) and apples was dispensed each morning
(8:00-10:00 A.M.), and the aimals fed themselves.
Water was allowed ad lib. up to 800 ml/day (4, 5).
Each chamber was fitted with a giant funnel to col-
lect urine. As the urine was excreted, it was sepa-
Psychosomatic Medicine Vol. 4 1 , No. 2 (March 1979)
Copyright " 1979 by the American Psychosomal
Published by Elsevier North Holland, Inc.
139
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M . J. PERLOW ET AL.
rated from the feces by a gauze filter, collected inplastic bottles (Nagle, Rochester, N. Y.), and im-mediately frozen at -40°C. 24-hour urines were sub-sequently stored at -1 0°C for 3 months. The first dayof urine collection began approximately 24 hoursafter the ketamine anesthesia and initiation of chairrestraint. For biochemical analysis, three consecu-tive 24-hour samples were defrosted and mixed to-gether with 15 ml of 10% disodium ethylenediaminetetraacetate. An aliquot of this mixture was refrozeri
(-80°C) and assayed 1-2 months later for total3-methoxy-4-hydroxyphenylethylglycol (MHPG),and free 3-methoxy-4-hydroxymandelic acid(VMA), 4-hydroxy-3-methoxyphenylacetic acid(HVA), and 3,4-dihydroxy phenylac etic acid(DOPAC) using gas chromatographic mass spectros-copic methodology (6). In these analyses deuteratedMHPG PH3-MHPG), DOPAC PHs-DOPAC), HVA(2H3-HVA), and VMA (2Hs-VMA) were used as inter-nal reference standards. 25 mg of each of these refer-ence standards was added to each sample at the be-ginning of the assay. To quantify the amount of thefree acid metabolites present in the samples, freeVMA, DOPAC, and HVA (25, 50, and 100 mg) wereadded to one urine sample in triplicate at the begin-ning of the analysis. From the difference between theamount of substance present in the urine with andwithout these latter standards, calibration curveswere constructed and used to quantify the amount offree acids present in each urine sam ple. The methylester pentafluoropropionyl derivatives of the acidmetabolites were prepared and analyzed (6).
For the quantification of total MHPG, the sulfateand glucuronide conjugates of MHPG were first hyd-rolyzed with a crude sulfatase preparation (SigmaChemical Co., St. Louis, Mo.) as previously reported(6). After hydrolysis, MHPG was extracted into ethylacetate and measured essentially as described for theacid metabolites. The pentafluoropropionyl deriva-tive was prepared for MHPG analysis.
Separation of the different metabolites wasachieved on an 8-ft 1-in i.d. steel column packedwith 3% SE 54 coated on 80/100 mesh chromosorb G(Pierce Chemical Co., Rockford 111.). A Finniganmodel 3200 quadrupole gas chromatograph massspectrometer was used. The fragments employedfor mass fragmentography were as previously re-ported (6).
RESULTS
The pattern of urinary excretion ofcatecholamine metabolites in the 3-day
period immediately after initiation ofchair restraint is presented in Table 1.Even after correction for body weight dif-ferences, there is considerable inter-mon-key variation in the rate of excretion of allfour m etabolites. For individual monkeys,the magnitude of the variation in excre-tion rates between the highest and lowest
rates for HVA, DOPAC, MHPG, and VMAis 2.7, 9.5, 1.7, and 2.9, respectively. Al-though there is no consistent correlationrelationship between the excretion ratesof each of the metabolites for individualanimals, the individual rate of excretionof the dopamine metabolites, HVA andDOPAC, is greater than the excretion ofthe norepinephrine and epinephrinemetabolites, VMA and MHPG, and theexcretion of MHPG is greater than theexcretion of VMA.
Using a repeated measure analysis of var-iance for a single factor, we are able todemonstrate a reduction in the excretionof 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 days19—21, the respective excretion rates ofMHPG, VMA, HVA, and DOPAC were68.7, 76.4, 67.5, and 77.2% of the ratesobserved on days 2-4. A Newman-Keulstest demonstrated a significant fp < 0.05)difference in the rates of excretion of
TABLE 1. Urinary Excretion of CatecholamineMetabolites in Monkeys Immediately After ChairRestraint (/xg/kg/24 hr)
Monkey
707
508
706854
842
Weight (kg)
5.1
5.65.2
6.0
7.0
HVA
835
419327
48 0
380
DOPAC
193
146
93
881
563
MHPG
123
80104
135
117
VM A
96
24
70
44
33
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CAT ECH OL AMIN ERC IC RESPONSE TO STRESS
MHPG, HVA, and DOPAC between days2-4 and days 19-21.
Body locomotor activity, although notspecifically monitored, appeared to beunchanged during the experimentalperiod. Dietary intake was measured dailyand was constant during the experimentalperiod, and for the 1-month period after
this investigation, during which the ani-mal remained restrained.
DISCUSSION
Various naturally occurring and ex-perimental paradigms have been used tostudy the catecholamine response to lifesituations, especially those considered tobe stressful (2, 3). A great many experi-ments have used rodents and subjectedthem to stress in the form of muscleexhaustion, environmental temperatureextremes, limb ischemia, electric shock,shaking, paradoxical sleep deprivation,swimming, hemorrhage, and immobiliza-tion (7-3 3). Although the actual concen-
Uj
IZ 8 0
• MHPG
O VMA
\ ^ A HVA
A OOPAC
0 5 10 15 20 25
DAYS
Fig. 1. Urinary excretion of catecholamine metabo-lites in monkeys after chair restraint. Valuesfor each metabolite is expressed as percentof quantity of metabolite excreted on days2 - 4 .
tration of catecholamines in brain tissuedid not consistently increase or decrease,the authors generally agreed thatnorepinephrine turnover in the brain wasincreased during acutely stressful situa-tions.
In situations where brain tissue couldnot be examined, as with most human
studies, catecholamine studies have reliedupon biochemical analyses of urine andblood. Most authors would agree thatconcentration changes of plasma and uri-nary catecholamines and catecholaminemetabolites reflect alterations in the turn-over rate of catecholamines. With stressesof various types the concentration ofnorepinephrine and epinephrine increase(2, 34-46). Representing only 0.5-6.0%of that released from synaptic nerve end-ings (40, 47-49), a fluctuation in theurine concentration of norepinephrineand epinephrine corresponds to similarchanges in the concentration of urinaryVMA (42, 47). For the 3-day period afterinitiation of chair restraint, monkeys ex-creted approximately 8 /u.g of epinephrineand norepinephrine per day (46, 50). Inthe experiment presented here, in simi-larly prepared animals, the monkeys ex-creted 946 fxg (range 581-1,120 /Ag) ofVMA and MHPG per day.
Chair restraint produced a threefold in-crease in urinary epinephrine and a
twofold increase in urinary norepinep-hrine (46,50). The urinary excretion ratesfor these compounds returned to stablebase-line levels after 1 week. The patternsof urinary norepinephrine and epinep-hrine excretion do not correspond to themore gradual reduction in the excretion ofMHPG or VMA. Urine MHPG and VMAexcretion rates declined 31.3 and 23.6%,respectively, over a 21-day period. Thecause for this difference in excretion isunknown but merits further study.
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The decline in norepinephrine metabo-lism may be the resu lt of adaptation to thephysical restraint itself, or, as a result ofprolonged social isolation and reductionof stimulation from environment. Socialisolation results in behavioral abnor-malities in monkeys (51) and, in rodents,is associated with a decrease in brain
dopamine and norepinephrine turnover,and a reduction in adrenal catecho-lamine-synthesizing enzymes (53-57).
"Stress" in rodents has been shown toalter the concentration and the turnover ofdopamine in brain tissue (7-11, 13, 14,18, 20, 22, 52, 58-61). Unlike no repinep-hrine, where there is a general agreementthat "stress" increases norepinephrineturnover, there is no concensus of opinionas to whether dopamine turnover in-creases, decreases, or remains unchangedin response to stress. This variation mayreflect variations in the strain of animalstudied, the stressor used, the intensityand duration of the stressor and the por-tion of the brain studied. As the monkeysadapted to the novel environment, theyexcreted smaller amounts of DOPAC andHVA, suggesting that over the 3-weekstudy period there was a reduction indopamine turnover. Because we are un-able to determine if the metabolities comefrom the central or the peripheral nervoussystem, we are unable to determine if
dopamine turnover in the brain decreasedduring chair adaptation.When normal volunteers or individuals
with psychiatric illnesses were exposed todifferent environmental situations, theyexcreted varying amounts of norepinep-hrine and epinephrine (2, 34, 35, 37-41,43, 48, 61). Analyses of these results haveled investigators to hypothesize that: (1)the concentrations and the ratio of urinaryepinephrine/norepinephrine response inan individual's behavioral state and the
manner in which he will respond to theinducing stimulus, and (2) thenorepinephrine and ep inephrine responseis a reflection of this general response tothe inducing stimulus. We had hoped thatour experiment would extend the observa-tions that serve as bases for these hypoth-eses (46,50). As a result of previous
studies in which norepinephrine weremeasured (46,50), we felt that the amountof urinary adrenergic metabolites wouldincrease with chair restraint. As urinaryVMA is considered to have its origin inpools of catecholamines outside the brainand urinary MHPG to have its origin inpools of norepinephrine in both the bodyand the brain (62), we postulated thattheir differential increase would reflectthe peripheral and central adrenergic re-sponse to the stressor. We also hoped thatas the animals adapted to the chair re-
straint and social isolation, and theamounts of catecholamine metabolitesdecreased, the ratio of VMA/MHPG wouldchange reflecting perhaps, a change inexcretion patterns of epinephrine andnorepinephrine, an alteration inmetabolic pathway for the metabolism ofepinephrine and/or norepinephrine, or adifferential rate of adaptation of the cen-tral vs. peripheral nervous systems to thestressor. Since the rate of decline of uri-nary excretion of MHPG and VMA was
similar, we were unable to speculate uponthe above propositions.
Despite a similarity of sexual gender,age, and body weight, there was consider-able variation between animals in excre-tion of catecholamine metabolites. A simi-lar variation was noted in earlier studiesmeasuring the excretion of catecho-lamines and catecholamine metabolites(2, 33-37, 40, 41, 45, 48, 61, 63-66). On akilogram basis, the variation betweenhighest and lowest excretion rates for
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CAT ECH OLA MINE RG IC RESPONSE TO STRESS
HVA, DOPAC, MHPG, an d VMA is dopaminergic metabolites decreases over2.7,9 .5,1.7 , and 2.9, res pe ctiv ely . Al- several weeks after initiation of chronicthough the ratio of MHPG/VMA is always chair restra int. Despite a considerable var-> 1, the ratio of HVA/DOPAC varies be- iation in base-line excretion rates, the ratetween 0.54 and 4.3. The relative excretion of decline of all metabolites is the same,rate of metabolites between animals and We note the possible usefulness in usingthe ratio of adrenergic and dopaminergic metabolites of catecholamines to followmetabolites in the urine was unchanged the biochemical response to a "stressor."
after 3 months of chair restraint (unpub-lished data). The authors wish to thank M. Strot-
From these results we conclude that the kamp and M. Adam s for their assistanceexcretion of adrenergic metabolites and in the preparation of this paper.
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