Cardiovascular Responses to Avoidance Conditioning in the Dog: Effects of Alpha Adrenergic Blockade DAVID E. ANDV.RSON, JotiN E. YINCLINC AND JOSEPH V. BRADY
The Johns llopkins Ut~iversity School o[ Medicine, Baltimore, Maryland
Abstract-Laboratory dogs were trained to press a response panel to postpone shocks during daily one-hour avoid:nice conditioning periods. Each dog was :dso confined iu the cxperinwntal environment for 5 hours prior to the avo!dancc pt'riods. Blood pressure and heart rate were monitored continuously during these experiments from chronically indwelling arterial catheters. Extended training resulted in the emergence of a cardiovascular response pattern during the pre-avoidance interval characterized by gradual increases in blood pressure together with decreases in heart rate. Elevations in both blood pressure and heart rate were sustained during the avoidance periods. During sessions in which alpha adrenergic activity was suppressed hy phenoxybenzamine, absolute levels of blo~;d pressure were found to be lower than during control (non-drug) sessions, but a progressive rise in blood pressure continued to be observed during pre-avoidance. These results suggest that sustained cardiovascular responses during avoidance periods are associated with activation of the sympathetic nervous system, but that the gradual rise in blood pressure during pre-avoidance is due to other factors.
CARDIOVASCULAREFFECTS Of avoidance conditioning have been investigated in several studies with laboratory dogs (Anderson and Brady, 1972; Anderson and Toshcff, 1973; lIouscr, 1974; Lawler, Obrist and Lawler, 1975) and primatcs (tlerd, et al. 1969; Forsyth, 1971; Findley, et al. 1971). These studies have shown that blood pressure elevations maintained during avoidance performance periods result from significant increases in heart rate and cardiac output, with total peripheral resistance rising significantly only in very extended sessions. Studies with drugs which suppress adreThis study was supported by National Heart and Lung Imtitute #HL 06945 and HL 17970.
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nergie receptor activity (Kelleher, Herd and Morse, 1972; Anderson and Brady, 1975) have implicated the sympathetic nervous system in the mediation of this acute cardiovascular response in both dogs and primates. Anofller pattern of cardiovascular response can be observed in dogs during confinement in tile experimental environment for fxed intervals immediately preceding avoidance sessions. During these pre-avoidance intervals, blood pressure rises gradually, systolic more than diastolic, due to progressive increases in total peripheral resistance, while heart rate and cardiac output decrease (Anderson and Tosheff, 1973). This pattern develops after extended training during which the dog learns to sit quietly in the chamber during the pre-avoidance interval, and initiate behavioral activity immediately after the onset of the avoidance contingency. Increases in blood pressure and decreases in heart rate have been observed to develop and recur over pre-avoidance intervals as long as 15 hours (Anderson and Brady, 1973) but did not develop during colafinement intervals immediately preceding sessions in which operant behavior was maintained by food reinforcement (Anderson and Brady, 1972). Bhx..kade of heta adrenergic activity by infusions of propranolol did not prevent the rise in pressure and fall in heart rate during pre-avoidance intervals, though it did significantly at.! tenuate the taehycardia wluch accompanied suhsequent avoidance performances (Anderson and Brady, 1975). The present study is concerned with the effects of blockade of alpha adrenergie activity upon cardiovascular patterns in dogs during pre-avoidance and avoidance intervals. It is generally agreed that alpha adrenergie receptors in the peripheral vasculatnre mediate sympaflwtic nervcms system effects upon peripheral resistance (Ahlquist, 1948). In the present experiments, blood pressure and heart rate patterns ohserved during pre-avoidance and awfidance in non-drug, control sessions were compared with blood pressure and heart rate patterns of tile same subjects during pre-avoidance and avoidance in other sessions during which alpha adrenergic activity was suppressed by infusions of phenoxybenzimline. Methods
Subpcts and Apparatus Four adult male mongrel dogs, weighing from 12 to 16 kg, served as subjects. Each was eonfilled in a specially-designed, flexible harness ill all experimental chamber (Anderson, et al. 1970) which pennitted fi'eedom of movement hut provided protection for cardiovascular monitoring equipment and shock electrodes. A
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translucent response panel (13 X 8 )< ;~ ram), mounted on tile front chamber wall, activated a microswitch adjusted to approxinmtely 15 grants of inward pressure and provided the recorded operant which enabled tile subjects to postpone the occurrence of electric shock. Illumination of the response key provided a visual stimulus for performance discrimination. A constant-current source (Swinnen, Brady and Powelll 1969) provided electrical stimulation which was" administered through stainless-steel electrodes to a shaved portion of the dog's rear leg. Sound attenuation and temperature control were facilitated by a blower and exhaust system mounted on the roof of the chamber. Food and water were freely available in the home cage between experimental sessions, and water was available in the chamber from a valve on the front dlamber wall. Behavioral Conditioning Procedures. Avoidance conditioning was accomplished after a period of adaptation to the restraint harness and experimental chamber. The avoidance procedure required the dog to postpone shocks by pressing the response key within a specified interval following a previous response (Sidman, 1953). Brief 60 Hz electric shocks (3-5 ma for 0.5 sec) were programmed every 20 see unless the dog pressed the panel within that interval and postponed the shock another 20 sec. The procedure generated stable panel-pressing behavior in each dog at rates of more than 15 per minute, thus avoiding all but an occasional shock (e.g. one per hour). The avoidance requirement was programmed during daily one-hour sessions, sigamlled by illumination of the response panel with a white light. A 5-hour pre-avoidance period was also programmed for each dog in the experimental chamber during which the response panel was not illuminated and no shocks were presented. Sessions were run 7 days per week, and training continued until panel-pressing behavior was initiated promptly ~ffter the onset of the panel light but before the occurrence of the first shock. Experimental stimuli were programmed and behavioral responses recorded automatically and remotely through the use of standard electronwdmnical relay circuitry. Cardiovasc,lar Monitoring Procedures. Following the development of stable behavioral performance, an arterial catheter was chronically implanted for monitoring of blood pressure and heart rate in subsequent experimental sessions. Each dog was anesthetized with sodium pentobarbitol (35 mg/kg) and ml 18-gauge polyvinyl chloride catheter inserted into the aorta, via either a femoral or carotid artery, using a modification of a technique employed by Perez-Cruet, Newton and Plumlee (1966). The catheter
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was externalized at the nape of the neck, filled with heparin, obturated, and protected by a leather collar worn in the home kennel. During experimental sessions, the catheter was attached to a Statham strain-gage ta-ansducer (P23de) which was affixed to the front yoke of the restraint harness. The transduced pressure signal was monitored on a Beckman dynograph (model 382) or, in some cases, a cathode ray oscilloscope, and maximal and minimal voltages corresponding to systolic and diastolic components of the pressure wave were stored in an electronic system (Swinnen, 1968) which provided on-line averages of systolic and diastolic pressure (mm Hg). An associated Schmitt trigger determined heart rate from the pressure signal, and heart })eats per minute were also printed out on-line. During these sessions, a slow infusion of lightly-heparinized saline (7 USP units/ml at a rate of approximately 12 ml/hr) using a Harvard peristaltic pump, facilitated continued patency of the catheter, Pharmacological Procedures. After the establishment of charaeteristic patterns of cardiovascular response during pre-avoidance and avoidance sessions over 7 successive daily sessions, as determined by inspection, an additional 7 sessions were run following infusions of phenoxybenzamine. Pilot work had previously shown that 1 mg/kg phenoxybenzamine, suppressed the effects upon pressure of a 0.25 ~g infusion of phenylephrine, and it has been reported that the biological half-life of phenoxybeuzamine is 24 hours (Goodman and Gilman, 1971). Accordingly, the alpha blocker was administered to the dog one hour before each of 7 successive sessipns. The behavioral and cardiovascular patterns obtained during these 7 drug sessions with each dog were analyzed in terms of averages over successive hourly intervals, and compared with averages for each cardiovascular measure recorded during the immediately preceding 7 sessions during which alpha adrenergie activity was not suppressed. Results
Cardiovascular Patterns During Control Sessions. Figure 1 shows mean levels of blood pressure and heart rate during successive hourly intervals of pre-avoidance and for the one-hour avoidance sessions, averaged over the total of 28 experiments under each condition (i.e., control and alpha blockade). From the beginning to the end of pre-avoidance in control sessions, systolic pressure increased an average of 9.7 mm Hg, diastolic pressure increased an average of 5.3 mm Hg and pulse pressure increased an average of rate decreased an average of 9.1 4.4 mm Itg. Concurrently, heart ' beats per minute. Table 1 shows that this divergent pattern of
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E T AL.
160
Systohr
14,5
BLOOD PRESSURE
130
(ram Hg)
t .........t ........ ........
.
.
.
.
.
.
.
90 Dmslohr
75
r / --~[
r
I ........ I""
I00
HEART
I
RATE
(bpm]
85
70
N=ZB -
- ConTrol
" - - " Phenoxybenzomme
I
2
3
4
5
6
Ttme in hours PRE-AVOIDANCE
AVOIDANCE
Ft(;. 1. Mean levels of systolic and diastolic pressure and heart rate during successive hourly intervals of the pre-avoidance period and the onehour avoidance period, averaged over 28 non-drug control sessions and 28 alpha blockade sessions for the group of four dogs.
blood pressure and heart rate change were observed on the average in each of the four dogs, and that the overall average changes were statistically significant. Figure 1 also shows that blood pressure and heart rate levels were significantly higher during the avoidance session than during the last hour of pre-avoidanee in control experiments. On the average, systolic pressure was increased 6.6 mm Hg, diastolic pressure increased 11.0 mm Hg, resulting in a decrease in pulse pressure of 4.4 mm Hg, which was the same mean value as recorded at the
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TABLZ 1. Mean Difference in Systolic and Diastolic Pressure and Heart Rate Between the First and l.alst Hour of Pre-avoklance, Averaged [or Each Subiect Across Non-drug Control Sessions and Alpha Blockade Sessions.
Control Subiect
Alpha Blockade
1 2 3 4
SP 7.7 9.8 9.8 11.1
DP 4.8 5.8 3.6 6.9
HR -10.3 - 6.7 -14.0 -5.3
SP 8.6 9.5 12.5 5.2
DP 3.3 5.3 7.2 1.6
HR -9.2 -6.9 -6.0 -3.8
X S.E. t
9.7 0.8 12.1
5.3 0.7 8.1
-9.1 1.8 5.2
8.4 1.2 7.1
4.4 0.8 5.6
-6.5 1.9 3.3
beginning of pre-avoidance (i.e. 67 m m H g . ) . In addition, heart rate during the avoidance periods was, on the average, 30.7 beats per minute greater than during the final pre-avoiJance hour. Table 2 shows that the increments in systolic and diastolic pressure associated with avoidance were c,bserved in three dogs, and that the tachycardia occurred in all four animals. Each of these difference scores was statistically significant for the group (Table 2).
Cardiovascular Patterns During Alpha Blockade Sessions. The broken lines in Figure 1 show the mean levels of each cardiovascular measure for each hour of the pre-avoidance period and for the avoidance period, in terms of an average over the total of 28 alpha blockade experiments. From the beginning to the end of pre-avoidTAm.z 2. Mean Difference in Systolic and I)iastolic Pressure (mm Hg) and Heart Rate (Beats/Min) Between the Last Htmr of Pre-avoidant~e aud the Avoidance Perfl~rmance Period, Averaged for Each Subject Across NonDrug Control Sessions and Alpha Blockade Sessions.
Control Subiect 1 2 3 4 X S.E. t
Alpha Blockade
SP 15.5 5.2 10.3 - 3.5
DP 21.4 10.0 17.7 - 3.5
HR 36.6 21.4 5.8 59.2
SP 5.0 - 0.9 2.4 - 6.5
DP 10.7 - 2.3 - 0.6 2.8
HR 32.0 2.9 - 13.2 33.0
6.8 2.9 2.3
11.0 1.3 8.1
30.7 3.6 8.5
0.2 1.3 0.1
2.6 1.3 1.9
11.3 3.9 2.9
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ance, systolic pressure increased an average of 8.4 mm tlg, diastolic pressure increased an average of 4.4 nun IIg, and pnlse pressure was therefore increased 4.4 mm Itg. Over the same period, heart rate decreased an average of 6.5 beats per minute. Table 1 shows that the direction of change in blood pressure and heart rate was also consistent between subjects in the drug experiments, and that in each case, the magnitude of change was statistically significant for the grdup. These progressive effects upon blood pressure and heart rate continued to be observed though systolic pressure during pre-avoidance in alpha blockade sessions was, on the average, 13.8 mm Hg lower than during pre-avoidance in control sessions (t --- 2.86; P < 0.01). Diastolic pressure and heart rate levels during the first hour of pre-avoidance in alpha blockade were found not to be sig||ifieantly different from levels during the first hour of pre-avoidance in control sessions, though for the entire 5-hour pre-avoidance interval, heart rate was significantly elevated above control session values (t = 4.72; P < 0.01). Figure 1 also shows that in alpha blockade experiments the levels of systolic and diastolic pressure during avoidance were not significantly increased above levels observed at the end of preavoidance. This phenomenon was consistent in three dogs (Table 2). In addition, heart rate levels during avoidance in alpha blockade sessions were, on the average, only 11.3 beats per minute increased above values observed at the end of pre-avoidance (t = 2.69; P < 0.01). This represents an average reduction in the magnitude of tachycardia accompanying avoidance of 73 per cent, compared with values observed in control experiments. Mean differences in heart rate between final pre-avoidance values and the average avoidance levels are documented for individual animals in Table 2, which shows consistent effects in all four subjects. Behavioral Effects of Alpha Blockade. Rates of panel-pressing behavior averaged 17.1 per minute during the 28 control sessions and 11.8 per minute during alpha blockade sessions. Consistent decreases in response rates were observed in 3 of the 4 dogs. The group decrease in avoidance response rate of 34.1 per cent was statistically significant (t = 3.08; P < 0.01). Concurrently, shock frequency increased from an average of 0.56 per hour during control sessions to 1.60 per hour during alpha blockade sessions.
Discussion Blockade of alpha adrenergie receptor activity in avoidancetrained dogs results in an attenuation of the sustained elevations in
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blood pressure and heart rate which accompany the performance of avoidance behavior, but does not attenuate the progressive increases in blood pressure and decreases in heart rate occurring during pre-avoidance periods. These data suggest that the sympathetic nervous system mediates the cardiovascular adaptation during avoidance performance periods, but that other factors mediate the cardiovascular changes occurring during pre-avoidance. The validity of this conclusion rests upon the effectiveness of the drug in suppressing alpha adrenergic activity. As evidence of the effectiveness of the dosage of phenoxybenzamine used in these experiments, three observations merit reiteration. First, 1 mg/kg doses of phenoxybenzamine will eliminate the pressor response to 0.25 vg/kg phenyephrine. Secondly, systolic pressure levels during alpha blockade sessions were consistently lower in each dog than during control sessions. Thirdly, the increment in systolic and diastolic pressure evoked by the onset of the avoidance stimulus in control sessions was not observed at the beginning of avoidance in alpha blockade sessions. These data strongly support the conclusion that the alpha adrenergie receptors were blocked in the drug experiments. Previous experiments with beta adrenergic blockers (Anderson and Brady, 1975) suggested that sympathetic tone upon the heart at the beginning of pre-avoidance was not significant. The administration of phenoxybenzamine in the present experiments resulted in lower values of systolic but not diastolic pressure during the first hour of pre-avoidance. Phenoxybenzamine is kno~m to decrease total peripheral resistance and increase cardiac output in the resting animal (Goodman and Gilman, 1971). The reduction in pulse pressure would be consistent with a decrease in total peripheral resistance, and the increase in heart rate would be consistent with an increase in cardiac output. The circulatory response involving decreases in heart rate and cardiac output and increases in total peripheral resistance and, in some cases, arterial blood pressure, has been investigated in a number of behavioral contexts, and appears to represent a fundamental hemodynanaic adaptation to a range of environmental demands. For example, the immersion of the head of a vertebrate in water results in a circulatory response characterized by marked and proportional decreases in heart rate and cardiac output and a very significant increase in total peripheral resistance (Andersen, 1966; Spencer, 1966). This diving reflex enables the organism to conserve oxygen for the heart and brain by redistributing blood away from the periphery, and, particularly, the skeletal musculature (Scholander, 1963). The reflex can be elicited in the anesthetized
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animal by electrical stimulation of the mesencephalon (Feigl and Folkow, 1963) and tile cardiac response, is mediated by an increase in vagal activity (Lin, 1974). In animals that do not naturally dive, such as tlle dog (tlong, et al. 1971) and mall (Mithoefer, 1965), an increase ill arterial l)Iood pressure is observed. Characteristic changes ill the electrocardiogram have also been observed during diving (Andersen, 1965). Orienting to a novel stimulus elicits a similar, though transient and less dramatic cardiovascular reflex, which includes cardiac deceleration, peripl)eral vasoconstriction, cephalic vasodilatation, depression of alpha EEG, and respiratory slowing (Sokolov, 1963). The reflex habituates after several presentations of the stimulus. A more stable response can be evoked by the presentation of a stimuhls with informational content; for example, the warning stimulus in a reaction time task, or a conditional stimulus preceding the occurrence of an electric shock (Obrist, 1973). These situations have been associated with a preparatory bradycardia accompanied by a cessation of somatic-motor behavior, and the cardiac response, has been associated with increases in vagal activity (Dykman and Gantt, 1959; Obrist, Webb and Perez-Reyes, 1965). Recently, it has been found that attentional behavior during a "sensory processing" task is accompanied by vasoconstriction in both the skin and skeletal muscles (Williams, et al. 1975). Similarly, cardiac deceleration and skeletal muscle vasoconstriction have been observed in cats during attentional behavior (Wenzel, 1959; Adams, et al. 1971). The pre-avoidance environment appears to generate attending behavior in dogs preparatory to the onset of the avoidance schedule. The pre-avoidance pattern does not emerge until the dog has learned to sit or lay quietly in the chamber until the avoidance signal is presented, and then begin to respond immediately after the panel light onset. Moreover, slowing of respiratory rate below levels observed in the resting animal before training is a typical feature of the pre-avoidauce adaptation. It has been suggested (e.g. Iterd, 1970; Williams, et al. 1975) that the increase in total peripheral resistance observed during diving or during attentional behavior may be mediated by activation of the sympathetic nervous system. The data from the present study are consistent with the hypothesis that the increase in total peripheral resistance and blood pressure during pre-avoidance are secondary to cholinergically-mediated shifts in skeletal-muscle blood flow, and that the rise.in pressure is due to the fact that the increase in total peripheral resistance is not adequately compensated for by the concomitant reduction in cardiac output. It seems possible that
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the physiological mechanisms mediating pre-avoidance cardiovascular responses are similar to those responsible for the circulatory changes observed in diving and orienting. The elevations in heart rate, cardiac output and arterial pressure which are maintained during avoidance sessions appear to be mediated by increases in sympathetic nervous system activity. This conclusion is consistent with the results of previous work on avoidance conditioning with dogs (Anderson and Brady, 1975) and primates (Kelleher, et al. 1972). The finding that plasma catecholamine levels are increased during avoidance performances is also in accord with this conclusion (Mason, Brady and Tolson, 1966). It has been suggested that the acute increases in blood pressure occurring in this context could participate in the pathogenesis of chronic hypertension in experimental animals (Forsyth, 1969; Herd, et al. 1969) and man, through structural changes in the peripheral vasculature engendered by repeated pressor episodes (Folkow and Nell, 1971). The acute cardiovascular response during pre-avoidance is hemodynamically similar to the chronic circulatory changes observed in essential hypertension (Page and McCubbins, 1968) and the possibility should be considered that sustained or repeated exposure to environmental conditions which elicit increases in total peripheral resistance acutely may over time result in structural accommodations of the peripheral vasculature such as occur in essential hypertension. Personality research (Harris and Forsyth, 1971) has indicated that individuals described as "tense" and "vigilant" are more likely to develop hypertension than control groups, and other studies (e.g. Doughtery, 1967; Morrison and Morris, 1959) have shown that occupations which require sustained vigilance are associated with increased incidence of hypertension. Additional animal research will be necessary to clarify the potential role of this vigilance reflex in the pathogenesis of hypertension, but, in any case, it will be instructive to determine the nature of the physiological processes mediating the acute changes in peripheral vascular function. Acknowledgments The authors wish to thank Robert Baer and Judith Stribling for their technical assistance, and Smith, Kline and French for the phenoxybenzamine used in these experiments. References Adams, D. B., Baceelli, 13,, Mancia, G. and Zanchetti, A.: Relation to cardiovascular changes in fighting to emotion and exercise. 1. Physiol. 212:321335, 1971.
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Ahlquist, R. P.: A study of the adrenotropic receptors. Am. I. Physiol., 153: 586-600, 1948. Atl(lt'rs('ll, II. T.: llyp~rpotasscmia aJJd el,~etr()eardit)graphic changes ill the (luck durillg prolonged diving. Acta Physiol. Scatld., 63:292-295, 1965. Andersen, H. T.: Physiological adaptatiol~s in diving vertebrates. Physiol. Rev., 46:212-243, 1966. Anderson, D. E. and Brady, J. V.: Differential preparatory, cardiovascular responses to aversive and appetitive behavioral conditioning. Cond. Reflex, 7:82-96, 1972. Anderson, 13. E. and Brady, J. V.: Prolonged preavoidance effects upon blood pressure and heart rate in the dog. Psychosom. icd., '}5:4-12, 1973. Anderson, D. E. and Br.ady J. V.: Cardiovascular resp.')lases to avoidance contioning in the dog: Effects of beta adrenergie blockade. Psychosom. Med. (in press). Anderson, D. E., Daley, L. A., Findley, J'. D. a,ld Brady, J. V.: A restraint system for the psychophysiological study of clogs. Behav. Res. MeCh. lnstru., 9:191.194, 197{). Anderson. I). E. aJ~d Toshcl[, J.: Cardiac output and total p~,riphcr~d resistance cha,~ges (hiring preavoi(l:mce periods in the clog. J. Aplflied PhysioL, 35: 650-654, 1973. Doughtery, J. D.: Cardiovascular findings in air traffic controllers. Aerospace ied., 38:26, 1967. Dykman, R. A. and Gantt, W. H.: The parasympathetic component of unlearned and acquired cardiac responses. 1. Comp. Physiol. Psychol., 59: 163-167, 1959. Feigl, E. and Folkow, B.: Cardiovascular responses in diving and during brain stimulation in ducks. Acta Physiol. Sc~nd., 57:99-110, 1963. Findley, J. D., l]rady, J. V., Robinson, W. W. and Gilliam, W..L: Continuous ~ardiovascular monitoring in the baboon d~tring long-term behavioral perhmnances. Co,mmn. Behalf. Biol., 6:49-58, 1971. l:(Jlk(Jw, B. ;utd Ncil, E.: Circltlalhm. Oxford Ui~iv. Press. I971. Forsyth, I1. P.: l$lo~)d pressure rc,sp~lls{~s in Itmg-tt'rm avoidance schcdldes in the rcstrailled rhesus monkey. Psychosonl. Med., 31:300-309, 1969. Forsyth, R. P.: Regional blood flow changes during 72-hour avoidance schedules in the monkey. Sc!(,tlce 173:546-548, 1971. Gantt, W. H.: Cardiovascular component of the conditional reflex to pain, food, and other stimuli. Physiol. Rev., 40:266-291. Goodman, L. and Gilman, A.: The Pharmacological Basis o[ Therapeutics. New York: Macmillan & Co., 1971. Harris, R. E. and Forsyth, R. P.: Personality and emotional stress in essential hypertension in man. The Ilahnemmm Symposi,m, 1971. Herd, J. A.: Overall regtdation of the circulation. Ann. Rev. Physiol., 32:289312, 1970. Herd, J. A., Mor~, W. H., Kdleher, R. T., and Jones, L. G.: Arterial hypertension in the squirrel monkey during 1)ehavioral experiments. Am. 1. Physiol., 217:24-29, 1969. Hong, S. K., Lin, Y. C., Lally, D. A., Yim, B. J. B., Kominami, N., Hong, P. W. and Moore, T. O.: Alveolar gas exchanges ~md cardiovascular fimctions during breath-holding with air. 1. Appl. Physiol., 30:540-547, 1971. I-Iouser, V. D. and Pare, W. P.: Long-term conditioned fear modification in the dog as measured by changes in urinary 11-hydroxycorticosteroid, heart rate and behavior. Pat;. I. Biol. Sci., 9:85-96, 1974.
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Kelleher, R., Morse, W. and Herd, J. A.: Effects of propranolol, phentolamine, and methylatropine on cardiovascular function in the squirrel monkey during behavioral experiments. J. Pharmacol. Exp. Ther., 182:204, 1972. Lawler, J. E., Orbist, P. A. and Lawler, K. A.: Cardiovascular function during preavoidance, avoidance and post-avoidance in dogs. Psychophysqology, 12:4-11, 1975. Lin, Y. C.: Autonomic nervous control of cardiovascular response during diving 9 " in the rat. Am. 1. Physiol., ,27:601-60a, 1974. Mason, J. W., Brady, J. V. and Tolson, W. W.: Behavioral adaptations and endocrine activity. In R. Levine (Ed.) Proceedings of the Association for Research in Nervous and Mental Diseases. Baltimore: Williams & Wilkins Co., 1966; pp. 227-248. Mithoefer, J. C.: Breath holding. Ilandbook of Physiology: Respiration. Washington, D. C.: American Physiological Society, 1965, Section 3, Volume 2, Chapter 38, 1965; pp. 1011-1025. Morrison, S. L. and Morris, J. N.: Epidemiological observations on high blood pressure without apparent cause. Lancet, ,:864-810, 1959. Obrist, P. A., Lawler, J. E. and Caebelein, J. C.: A psychobiological perspective on the cardiovascular system. In L. V. DiCara (Ed.) Advances in Limbic and Autonomic Nervous System Research. New York: Plenum Press, 1973; pp. 311-334. Obrist, P. A., Wood, D. M. and Perez-Reyes, M.: Heart rate during conditioning in humans: Effects of UCS intensity, vagal blockade, and adrenergic block of vasomotor activity. 1. Exp. Psychol., 70:32-42, 1965. Page, I. H. and McCubbin, J. W.: The physiology of arterial hypertension. Handbook of Physiology: Circldation. Washington, D. C.: American Physiological Society, Section 2, Volume 3, 1965; pp. 2163-2208. Perez-Cruet, J., Plumlee, L. A. and Newton, J. E. O.: Chronic basal blood pressure in unanesthetized dogs using the ring-catheter technique. Proc. Syrup. Biomed. Engr., i:383-386, 1966. Scholander, P. F.: The masterswitch of life. Sci. Am., 209:92-106, 1963. Sidman, M.: Avoidance conditioning with brief shock and no exteroceptive warning signal. Science, 118:157-158, 1953. Sokolov, E. N.: Perception and the conditioned reflex. Oxford: Pergamon Press, 1963. Spencer, M. P.: Systemic circulation. Ann. Rev. Physiol., 28:311-346, 1966. Swinnen, M. E. T.: Blood pressure digitizer. Proc. Ann. Conf. Engr. Med. Biol., 10:18, 1968. Swinnen, M. E. T., Brady, J. V. and Powell, M. G.: A new device for the application of electrical shock. Behav. Res. Meth. Instru., 1:184, 1969. Williams, R. B., Bittker, T. E., Buchsbaum, M. S. and Wynne, L. C.: Cardiovascular and neurophysiologie correlates of sensory intake and rejection. I. Effect of cognitive tasks. Psychophysiology, 19:427-433, 1975.
The Johns llopkins Ut~iversity School o[ Medicine, Baltimore, Maryland
Abstract-Laboratory dogs were trained to press a response panel to postpone shocks during daily one-hour avoid:nice conditioning periods. Each dog was :dso confined iu the cxperinwntal environment for 5 hours prior to the avo!dancc pt'riods. Blood pressure and heart rate were monitored continuously during these experiments from chronically indwelling arterial catheters. Extended training resulted in the emergence of a cardiovascular response pattern during the pre-avoidance interval characterized by gradual increases in blood pressure together with decreases in heart rate. Elevations in both blood pressure and heart rate were sustained during the avoidance periods. During sessions in which alpha adrenergic activity was suppressed hy phenoxybenzamine, absolute levels of blo~;d pressure were found to be lower than during control (non-drug) sessions, but a progressive rise in blood pressure continued to be observed during pre-avoidance. These results suggest that sustained cardiovascular responses during avoidance periods are associated with activation of the sympathetic nervous system, but that the gradual rise in blood pressure during pre-avoidance is due to other factors.
CARDIOVASCULAREFFECTS Of avoidance conditioning have been investigated in several studies with laboratory dogs (Anderson and Brady, 1972; Anderson and Toshcff, 1973; lIouscr, 1974; Lawler, Obrist and Lawler, 1975) and primatcs (tlerd, et al. 1969; Forsyth, 1971; Findley, et al. 1971). These studies have shown that blood pressure elevations maintained during avoidance performance periods result from significant increases in heart rate and cardiac output, with total peripheral resistance rising significantly only in very extended sessions. Studies with drugs which suppress adreThis study was supported by National Heart and Lung Imtitute #HL 06945 and HL 17970.
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nergie receptor activity (Kelleher, Herd and Morse, 1972; Anderson and Brady, 1975) have implicated the sympathetic nervous system in the mediation of this acute cardiovascular response in both dogs and primates. Anofller pattern of cardiovascular response can be observed in dogs during confinement in tile experimental environment for fxed intervals immediately preceding avoidance sessions. During these pre-avoidance intervals, blood pressure rises gradually, systolic more than diastolic, due to progressive increases in total peripheral resistance, while heart rate and cardiac output decrease (Anderson and Tosheff, 1973). This pattern develops after extended training during which the dog learns to sit quietly in the chamber during the pre-avoidance interval, and initiate behavioral activity immediately after the onset of the avoidance contingency. Increases in blood pressure and decreases in heart rate have been observed to develop and recur over pre-avoidance intervals as long as 15 hours (Anderson and Brady, 1973) but did not develop during colafinement intervals immediately preceding sessions in which operant behavior was maintained by food reinforcement (Anderson and Brady, 1972). Bhx..kade of heta adrenergic activity by infusions of propranolol did not prevent the rise in pressure and fall in heart rate during pre-avoidance intervals, though it did significantly at.! tenuate the taehycardia wluch accompanied suhsequent avoidance performances (Anderson and Brady, 1975). The present study is concerned with the effects of blockade of alpha adrenergie activity upon cardiovascular patterns in dogs during pre-avoidance and avoidance intervals. It is generally agreed that alpha adrenergie receptors in the peripheral vasculatnre mediate sympaflwtic nervcms system effects upon peripheral resistance (Ahlquist, 1948). In the present experiments, blood pressure and heart rate patterns ohserved during pre-avoidance and awfidance in non-drug, control sessions were compared with blood pressure and heart rate patterns of tile same subjects during pre-avoidance and avoidance in other sessions during which alpha adrenergic activity was suppressed by infusions of phenoxybenzimline. Methods
Subpcts and Apparatus Four adult male mongrel dogs, weighing from 12 to 16 kg, served as subjects. Each was eonfilled in a specially-designed, flexible harness ill all experimental chamber (Anderson, et al. 1970) which pennitted fi'eedom of movement hut provided protection for cardiovascular monitoring equipment and shock electrodes. A
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translucent response panel (13 X 8 )< ;~ ram), mounted on tile front chamber wall, activated a microswitch adjusted to approxinmtely 15 grants of inward pressure and provided the recorded operant which enabled tile subjects to postpone the occurrence of electric shock. Illumination of the response key provided a visual stimulus for performance discrimination. A constant-current source (Swinnen, Brady and Powelll 1969) provided electrical stimulation which was" administered through stainless-steel electrodes to a shaved portion of the dog's rear leg. Sound attenuation and temperature control were facilitated by a blower and exhaust system mounted on the roof of the chamber. Food and water were freely available in the home cage between experimental sessions, and water was available in the chamber from a valve on the front dlamber wall. Behavioral Conditioning Procedures. Avoidance conditioning was accomplished after a period of adaptation to the restraint harness and experimental chamber. The avoidance procedure required the dog to postpone shocks by pressing the response key within a specified interval following a previous response (Sidman, 1953). Brief 60 Hz electric shocks (3-5 ma for 0.5 sec) were programmed every 20 see unless the dog pressed the panel within that interval and postponed the shock another 20 sec. The procedure generated stable panel-pressing behavior in each dog at rates of more than 15 per minute, thus avoiding all but an occasional shock (e.g. one per hour). The avoidance requirement was programmed during daily one-hour sessions, sigamlled by illumination of the response panel with a white light. A 5-hour pre-avoidance period was also programmed for each dog in the experimental chamber during which the response panel was not illuminated and no shocks were presented. Sessions were run 7 days per week, and training continued until panel-pressing behavior was initiated promptly ~ffter the onset of the panel light but before the occurrence of the first shock. Experimental stimuli were programmed and behavioral responses recorded automatically and remotely through the use of standard electronwdmnical relay circuitry. Cardiovasc,lar Monitoring Procedures. Following the development of stable behavioral performance, an arterial catheter was chronically implanted for monitoring of blood pressure and heart rate in subsequent experimental sessions. Each dog was anesthetized with sodium pentobarbitol (35 mg/kg) and ml 18-gauge polyvinyl chloride catheter inserted into the aorta, via either a femoral or carotid artery, using a modification of a technique employed by Perez-Cruet, Newton and Plumlee (1966). The catheter
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was externalized at the nape of the neck, filled with heparin, obturated, and protected by a leather collar worn in the home kennel. During experimental sessions, the catheter was attached to a Statham strain-gage ta-ansducer (P23de) which was affixed to the front yoke of the restraint harness. The transduced pressure signal was monitored on a Beckman dynograph (model 382) or, in some cases, a cathode ray oscilloscope, and maximal and minimal voltages corresponding to systolic and diastolic components of the pressure wave were stored in an electronic system (Swinnen, 1968) which provided on-line averages of systolic and diastolic pressure (mm Hg). An associated Schmitt trigger determined heart rate from the pressure signal, and heart })eats per minute were also printed out on-line. During these sessions, a slow infusion of lightly-heparinized saline (7 USP units/ml at a rate of approximately 12 ml/hr) using a Harvard peristaltic pump, facilitated continued patency of the catheter, Pharmacological Procedures. After the establishment of charaeteristic patterns of cardiovascular response during pre-avoidance and avoidance sessions over 7 successive daily sessions, as determined by inspection, an additional 7 sessions were run following infusions of phenoxybenzamine. Pilot work had previously shown that 1 mg/kg phenoxybenzamine, suppressed the effects upon pressure of a 0.25 ~g infusion of phenylephrine, and it has been reported that the biological half-life of phenoxybeuzamine is 24 hours (Goodman and Gilman, 1971). Accordingly, the alpha blocker was administered to the dog one hour before each of 7 successive sessipns. The behavioral and cardiovascular patterns obtained during these 7 drug sessions with each dog were analyzed in terms of averages over successive hourly intervals, and compared with averages for each cardiovascular measure recorded during the immediately preceding 7 sessions during which alpha adrenergie activity was not suppressed. Results
Cardiovascular Patterns During Control Sessions. Figure 1 shows mean levels of blood pressure and heart rate during successive hourly intervals of pre-avoidance and for the one-hour avoidance sessions, averaged over the total of 28 experiments under each condition (i.e., control and alpha blockade). From the beginning to the end of pre-avoidance in control sessions, systolic pressure increased an average of 9.7 mm Hg, diastolic pressure increased an average of 5.3 mm Hg and pulse pressure increased an average of rate decreased an average of 9.1 4.4 mm Itg. Concurrently, heart ' beats per minute. Table 1 shows that this divergent pattern of
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E T AL.
160
Systohr
14,5
BLOOD PRESSURE
130
(ram Hg)
t .........t ........ ........
.
.
.
.
.
.
.
90 Dmslohr
75
r / --~[
r
I ........ I""
I00
HEART
I
RATE
(bpm]
85
70
N=ZB -
- ConTrol
" - - " Phenoxybenzomme
I
2
3
4
5
6
Ttme in hours PRE-AVOIDANCE
AVOIDANCE
Ft(;. 1. Mean levels of systolic and diastolic pressure and heart rate during successive hourly intervals of the pre-avoidance period and the onehour avoidance period, averaged over 28 non-drug control sessions and 28 alpha blockade sessions for the group of four dogs.
blood pressure and heart rate change were observed on the average in each of the four dogs, and that the overall average changes were statistically significant. Figure 1 also shows that blood pressure and heart rate levels were significantly higher during the avoidance session than during the last hour of pre-avoidanee in control experiments. On the average, systolic pressure was increased 6.6 mm Hg, diastolic pressure increased 11.0 mm Hg, resulting in a decrease in pulse pressure of 4.4 mm Hg, which was the same mean value as recorded at the
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TABLZ 1. Mean Difference in Systolic and Diastolic Pressure and Heart Rate Between the First and l.alst Hour of Pre-avoklance, Averaged [or Each Subiect Across Non-drug Control Sessions and Alpha Blockade Sessions.
Control Subiect
Alpha Blockade
1 2 3 4
SP 7.7 9.8 9.8 11.1
DP 4.8 5.8 3.6 6.9
HR -10.3 - 6.7 -14.0 -5.3
SP 8.6 9.5 12.5 5.2
DP 3.3 5.3 7.2 1.6
HR -9.2 -6.9 -6.0 -3.8
X S.E. t
9.7 0.8 12.1
5.3 0.7 8.1
-9.1 1.8 5.2
8.4 1.2 7.1
4.4 0.8 5.6
-6.5 1.9 3.3
beginning of pre-avoidance (i.e. 67 m m H g . ) . In addition, heart rate during the avoidance periods was, on the average, 30.7 beats per minute greater than during the final pre-avoiJance hour. Table 2 shows that the increments in systolic and diastolic pressure associated with avoidance were c,bserved in three dogs, and that the tachycardia occurred in all four animals. Each of these difference scores was statistically significant for the group (Table 2).
Cardiovascular Patterns During Alpha Blockade Sessions. The broken lines in Figure 1 show the mean levels of each cardiovascular measure for each hour of the pre-avoidance period and for the avoidance period, in terms of an average over the total of 28 alpha blockade experiments. From the beginning to the end of pre-avoidTAm.z 2. Mean Difference in Systolic and I)iastolic Pressure (mm Hg) and Heart Rate (Beats/Min) Between the Last Htmr of Pre-avoidant~e aud the Avoidance Perfl~rmance Period, Averaged for Each Subject Across NonDrug Control Sessions and Alpha Blockade Sessions.
Control Subiect 1 2 3 4 X S.E. t
Alpha Blockade
SP 15.5 5.2 10.3 - 3.5
DP 21.4 10.0 17.7 - 3.5
HR 36.6 21.4 5.8 59.2
SP 5.0 - 0.9 2.4 - 6.5
DP 10.7 - 2.3 - 0.6 2.8
HR 32.0 2.9 - 13.2 33.0
6.8 2.9 2.3
11.0 1.3 8.1
30.7 3.6 8.5
0.2 1.3 0.1
2.6 1.3 1.9
11.3 3.9 2.9
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ance, systolic pressure increased an average of 8.4 mm tlg, diastolic pressure increased an average of 4.4 nun IIg, and pnlse pressure was therefore increased 4.4 mm Itg. Over the same period, heart rate decreased an average of 6.5 beats per minute. Table 1 shows that the direction of change in blood pressure and heart rate was also consistent between subjects in the drug experiments, and that in each case, the magnitude of change was statistically significant for the grdup. These progressive effects upon blood pressure and heart rate continued to be observed though systolic pressure during pre-avoidance in alpha blockade sessions was, on the average, 13.8 mm Hg lower than during pre-avoidance in control sessions (t --- 2.86; P < 0.01). Diastolic pressure and heart rate levels during the first hour of pre-avoidance in alpha blockade were found not to be sig||ifieantly different from levels during the first hour of pre-avoidance in control sessions, though for the entire 5-hour pre-avoidance interval, heart rate was significantly elevated above control session values (t = 4.72; P < 0.01). Figure 1 also shows that in alpha blockade experiments the levels of systolic and diastolic pressure during avoidance were not significantly increased above levels observed at the end of preavoidance. This phenomenon was consistent in three dogs (Table 2). In addition, heart rate levels during avoidance in alpha blockade sessions were, on the average, only 11.3 beats per minute increased above values observed at the end of pre-avoidance (t = 2.69; P < 0.01). This represents an average reduction in the magnitude of tachycardia accompanying avoidance of 73 per cent, compared with values observed in control experiments. Mean differences in heart rate between final pre-avoidance values and the average avoidance levels are documented for individual animals in Table 2, which shows consistent effects in all four subjects. Behavioral Effects of Alpha Blockade. Rates of panel-pressing behavior averaged 17.1 per minute during the 28 control sessions and 11.8 per minute during alpha blockade sessions. Consistent decreases in response rates were observed in 3 of the 4 dogs. The group decrease in avoidance response rate of 34.1 per cent was statistically significant (t = 3.08; P < 0.01). Concurrently, shock frequency increased from an average of 0.56 per hour during control sessions to 1.60 per hour during alpha blockade sessions.
Discussion Blockade of alpha adrenergie receptor activity in avoidancetrained dogs results in an attenuation of the sustained elevations in
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blood pressure and heart rate which accompany the performance of avoidance behavior, but does not attenuate the progressive increases in blood pressure and decreases in heart rate occurring during pre-avoidance periods. These data suggest that the sympathetic nervous system mediates the cardiovascular adaptation during avoidance performance periods, but that other factors mediate the cardiovascular changes occurring during pre-avoidance. The validity of this conclusion rests upon the effectiveness of the drug in suppressing alpha adrenergic activity. As evidence of the effectiveness of the dosage of phenoxybenzamine used in these experiments, three observations merit reiteration. First, 1 mg/kg doses of phenoxybenzamine will eliminate the pressor response to 0.25 vg/kg phenyephrine. Secondly, systolic pressure levels during alpha blockade sessions were consistently lower in each dog than during control sessions. Thirdly, the increment in systolic and diastolic pressure evoked by the onset of the avoidance stimulus in control sessions was not observed at the beginning of avoidance in alpha blockade sessions. These data strongly support the conclusion that the alpha adrenergie receptors were blocked in the drug experiments. Previous experiments with beta adrenergic blockers (Anderson and Brady, 1975) suggested that sympathetic tone upon the heart at the beginning of pre-avoidance was not significant. The administration of phenoxybenzamine in the present experiments resulted in lower values of systolic but not diastolic pressure during the first hour of pre-avoidance. Phenoxybenzamine is kno~m to decrease total peripheral resistance and increase cardiac output in the resting animal (Goodman and Gilman, 1971). The reduction in pulse pressure would be consistent with a decrease in total peripheral resistance, and the increase in heart rate would be consistent with an increase in cardiac output. The circulatory response involving decreases in heart rate and cardiac output and increases in total peripheral resistance and, in some cases, arterial blood pressure, has been investigated in a number of behavioral contexts, and appears to represent a fundamental hemodynanaic adaptation to a range of environmental demands. For example, the immersion of the head of a vertebrate in water results in a circulatory response characterized by marked and proportional decreases in heart rate and cardiac output and a very significant increase in total peripheral resistance (Andersen, 1966; Spencer, 1966). This diving reflex enables the organism to conserve oxygen for the heart and brain by redistributing blood away from the periphery, and, particularly, the skeletal musculature (Scholander, 1963). The reflex can be elicited in the anesthetized
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animal by electrical stimulation of the mesencephalon (Feigl and Folkow, 1963) and tile cardiac response, is mediated by an increase in vagal activity (Lin, 1974). In animals that do not naturally dive, such as tlle dog (tlong, et al. 1971) and mall (Mithoefer, 1965), an increase ill arterial l)Iood pressure is observed. Characteristic changes ill the electrocardiogram have also been observed during diving (Andersen, 1965). Orienting to a novel stimulus elicits a similar, though transient and less dramatic cardiovascular reflex, which includes cardiac deceleration, peripl)eral vasoconstriction, cephalic vasodilatation, depression of alpha EEG, and respiratory slowing (Sokolov, 1963). The reflex habituates after several presentations of the stimulus. A more stable response can be evoked by the presentation of a stimuhls with informational content; for example, the warning stimulus in a reaction time task, or a conditional stimulus preceding the occurrence of an electric shock (Obrist, 1973). These situations have been associated with a preparatory bradycardia accompanied by a cessation of somatic-motor behavior, and the cardiac response, has been associated with increases in vagal activity (Dykman and Gantt, 1959; Obrist, Webb and Perez-Reyes, 1965). Recently, it has been found that attentional behavior during a "sensory processing" task is accompanied by vasoconstriction in both the skin and skeletal muscles (Williams, et al. 1975). Similarly, cardiac deceleration and skeletal muscle vasoconstriction have been observed in cats during attentional behavior (Wenzel, 1959; Adams, et al. 1971). The pre-avoidance environment appears to generate attending behavior in dogs preparatory to the onset of the avoidance schedule. The pre-avoidance pattern does not emerge until the dog has learned to sit or lay quietly in the chamber until the avoidance signal is presented, and then begin to respond immediately after the panel light onset. Moreover, slowing of respiratory rate below levels observed in the resting animal before training is a typical feature of the pre-avoidauce adaptation. It has been suggested (e.g. Iterd, 1970; Williams, et al. 1975) that the increase in total peripheral resistance observed during diving or during attentional behavior may be mediated by activation of the sympathetic nervous system. The data from the present study are consistent with the hypothesis that the increase in total peripheral resistance and blood pressure during pre-avoidance are secondary to cholinergically-mediated shifts in skeletal-muscle blood flow, and that the rise.in pressure is due to the fact that the increase in total peripheral resistance is not adequately compensated for by the concomitant reduction in cardiac output. It seems possible that
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the physiological mechanisms mediating pre-avoidance cardiovascular responses are similar to those responsible for the circulatory changes observed in diving and orienting. The elevations in heart rate, cardiac output and arterial pressure which are maintained during avoidance sessions appear to be mediated by increases in sympathetic nervous system activity. This conclusion is consistent with the results of previous work on avoidance conditioning with dogs (Anderson and Brady, 1975) and primates (Kelleher, et al. 1972). The finding that plasma catecholamine levels are increased during avoidance performances is also in accord with this conclusion (Mason, Brady and Tolson, 1966). It has been suggested that the acute increases in blood pressure occurring in this context could participate in the pathogenesis of chronic hypertension in experimental animals (Forsyth, 1969; Herd, et al. 1969) and man, through structural changes in the peripheral vasculature engendered by repeated pressor episodes (Folkow and Nell, 1971). The acute cardiovascular response during pre-avoidance is hemodynamically similar to the chronic circulatory changes observed in essential hypertension (Page and McCubbins, 1968) and the possibility should be considered that sustained or repeated exposure to environmental conditions which elicit increases in total peripheral resistance acutely may over time result in structural accommodations of the peripheral vasculature such as occur in essential hypertension. Personality research (Harris and Forsyth, 1971) has indicated that individuals described as "tense" and "vigilant" are more likely to develop hypertension than control groups, and other studies (e.g. Doughtery, 1967; Morrison and Morris, 1959) have shown that occupations which require sustained vigilance are associated with increased incidence of hypertension. Additional animal research will be necessary to clarify the potential role of this vigilance reflex in the pathogenesis of hypertension, but, in any case, it will be instructive to determine the nature of the physiological processes mediating the acute changes in peripheral vascular function. Acknowledgments The authors wish to thank Robert Baer and Judith Stribling for their technical assistance, and Smith, Kline and French for the phenoxybenzamine used in these experiments. References Adams, D. B., Baceelli, 13,, Mancia, G. and Zanchetti, A.: Relation to cardiovascular changes in fighting to emotion and exercise. 1. Physiol. 212:321335, 1971.
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Ahlquist, R. P.: A study of the adrenotropic receptors. Am. I. Physiol., 153: 586-600, 1948. Atl(lt'rs('ll, II. T.: llyp~rpotasscmia aJJd el,~etr()eardit)graphic changes ill the (luck durillg prolonged diving. Acta Physiol. Scatld., 63:292-295, 1965. Andersen, H. T.: Physiological adaptatiol~s in diving vertebrates. Physiol. Rev., 46:212-243, 1966. Anderson, D. E. and Brady, J. V.: Differential preparatory, cardiovascular responses to aversive and appetitive behavioral conditioning. Cond. Reflex, 7:82-96, 1972. Anderson, 13. E. and Brady, J. V.: Prolonged preavoidance effects upon blood pressure and heart rate in the dog. Psychosom. icd., '}5:4-12, 1973. Anderson, D. E. and Br.ady J. V.: Cardiovascular resp.')lases to avoidance contioning in the dog: Effects of beta adrenergie blockade. Psychosom. Med. (in press). Anderson, D. E., Daley, L. A., Findley, J'. D. a,ld Brady, J. V.: A restraint system for the psychophysiological study of clogs. Behav. Res. MeCh. lnstru., 9:191.194, 197{). Anderson. I). E. aJ~d Toshcl[, J.: Cardiac output and total p~,riphcr~d resistance cha,~ges (hiring preavoi(l:mce periods in the clog. J. Aplflied PhysioL, 35: 650-654, 1973. Doughtery, J. D.: Cardiovascular findings in air traffic controllers. Aerospace ied., 38:26, 1967. Dykman, R. A. and Gantt, W. H.: The parasympathetic component of unlearned and acquired cardiac responses. 1. Comp. Physiol. Psychol., 59: 163-167, 1959. Feigl, E. and Folkow, B.: Cardiovascular responses in diving and during brain stimulation in ducks. Acta Physiol. Sc~nd., 57:99-110, 1963. Findley, J. D., l]rady, J. V., Robinson, W. W. and Gilliam, W..L: Continuous ~ardiovascular monitoring in the baboon d~tring long-term behavioral perhmnances. Co,mmn. Behalf. Biol., 6:49-58, 1971. l:(Jlk(Jw, B. ;utd Ncil, E.: Circltlalhm. Oxford Ui~iv. Press. I971. Forsyth, I1. P.: l$lo~)d pressure rc,sp~lls{~s in Itmg-tt'rm avoidance schcdldes in the rcstrailled rhesus monkey. Psychosonl. Med., 31:300-309, 1969. Forsyth, R. P.: Regional blood flow changes during 72-hour avoidance schedules in the monkey. Sc!(,tlce 173:546-548, 1971. Gantt, W. H.: Cardiovascular component of the conditional reflex to pain, food, and other stimuli. Physiol. Rev., 40:266-291. Goodman, L. and Gilman, A.: The Pharmacological Basis o[ Therapeutics. New York: Macmillan & Co., 1971. Harris, R. E. and Forsyth, R. P.: Personality and emotional stress in essential hypertension in man. The Ilahnemmm Symposi,m, 1971. Herd, J. A.: Overall regtdation of the circulation. Ann. Rev. Physiol., 32:289312, 1970. Herd, J. A., Mor~, W. H., Kdleher, R. T., and Jones, L. G.: Arterial hypertension in the squirrel monkey during 1)ehavioral experiments. Am. 1. Physiol., 217:24-29, 1969. Hong, S. K., Lin, Y. C., Lally, D. A., Yim, B. J. B., Kominami, N., Hong, P. W. and Moore, T. O.: Alveolar gas exchanges ~md cardiovascular fimctions during breath-holding with air. 1. Appl. Physiol., 30:540-547, 1971. I-Iouser, V. D. and Pare, W. P.: Long-term conditioned fear modification in the dog as measured by changes in urinary 11-hydroxycorticosteroid, heart rate and behavior. Pat;. I. Biol. Sci., 9:85-96, 1974.
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Kelleher, R., Morse, W. and Herd, J. A.: Effects of propranolol, phentolamine, and methylatropine on cardiovascular function in the squirrel monkey during behavioral experiments. J. Pharmacol. Exp. Ther., 182:204, 1972. Lawler, J. E., Orbist, P. A. and Lawler, K. A.: Cardiovascular function during preavoidance, avoidance and post-avoidance in dogs. Psychophysqology, 12:4-11, 1975. Lin, Y. C.: Autonomic nervous control of cardiovascular response during diving 9 " in the rat. Am. 1. Physiol., ,27:601-60a, 1974. Mason, J. W., Brady, J. V. and Tolson, W. W.: Behavioral adaptations and endocrine activity. In R. Levine (Ed.) Proceedings of the Association for Research in Nervous and Mental Diseases. Baltimore: Williams & Wilkins Co., 1966; pp. 227-248. Mithoefer, J. C.: Breath holding. Ilandbook of Physiology: Respiration. Washington, D. C.: American Physiological Society, 1965, Section 3, Volume 2, Chapter 38, 1965; pp. 1011-1025. Morrison, S. L. and Morris, J. N.: Epidemiological observations on high blood pressure without apparent cause. Lancet, ,:864-810, 1959. Obrist, P. A., Lawler, J. E. and Caebelein, J. C.: A psychobiological perspective on the cardiovascular system. In L. V. DiCara (Ed.) Advances in Limbic and Autonomic Nervous System Research. New York: Plenum Press, 1973; pp. 311-334. Obrist, P. A., Wood, D. M. and Perez-Reyes, M.: Heart rate during conditioning in humans: Effects of UCS intensity, vagal blockade, and adrenergic block of vasomotor activity. 1. Exp. Psychol., 70:32-42, 1965. Page, I. H. and McCubbin, J. W.: The physiology of arterial hypertension. Handbook of Physiology: Circldation. Washington, D. C.: American Physiological Society, Section 2, Volume 3, 1965; pp. 2163-2208. Perez-Cruet, J., Plumlee, L. A. and Newton, J. E. O.: Chronic basal blood pressure in unanesthetized dogs using the ring-catheter technique. Proc. Syrup. Biomed. Engr., i:383-386, 1966. Scholander, P. F.: The masterswitch of life. Sci. Am., 209:92-106, 1963. Sidman, M.: Avoidance conditioning with brief shock and no exteroceptive warning signal. Science, 118:157-158, 1953. Sokolov, E. N.: Perception and the conditioned reflex. Oxford: Pergamon Press, 1963. Spencer, M. P.: Systemic circulation. Ann. Rev. Physiol., 28:311-346, 1966. Swinnen, M. E. T.: Blood pressure digitizer. Proc. Ann. Conf. Engr. Med. Biol., 10:18, 1968. Swinnen, M. E. T., Brady, J. V. and Powell, M. G.: A new device for the application of electrical shock. Behav. Res. Meth. Instru., 1:184, 1969. Williams, R. B., Bittker, T. E., Buchsbaum, M. S. and Wynne, L. C.: Cardiovascular and neurophysiologie correlates of sensory intake and rejection. I. Effect of cognitive tasks. Psychophysiology, 19:427-433, 1975.
