9A7'/V
THE EFFECT OF HYPOTHALAMIC STIMULATION
ON THE PHAGOCYTIC ACTIVITY OF THE
RETICULOENDOTHELIAL SYSTEM
THESIS
Presented to the Graduate Council of the
North Texas State University in Partial
Fulfillment of the Requirements
For the Degree of
MASTER OF SCIENCE
By
Paul Louis Lambert, B. A,
Denton, Texas
December, 1979
Lambert, Paul Louis, The Effect of Hypothalamic Stimulation on
the Phagocytic Actvity of the Reticuloendothelial System. Master of
Science (Experimental Psychology), December, 1979, 26 pp., 1 table,
1 illustration, references, 41 titles.
Although research has linked the central nervous system with
changes in immunoresponsivity, research on the possible role of the central
nervous system in altering reticuloendothelial activity is lacking. This
study investigated the possible relationship between hypothalamic structures
and changes in responsivity of the reticuloendothelial system.
Eight male albino rats received bilateral electrode implants in
the ventromedial area of the hypothalamus and, following brain stimulation,
reticuloendothelial activity was assessed 3, 6, 12, 24, and 96 hours
after stimulation. Brain stimulation decreased phagocytic activity of
the reticuloendothelial system. These findings may increase our understanding
of a possible neural mechanism underlying relationships between stress
and resistance to disease states.
TABLE OF CONTENTS
Page
LIST OF TABLES, . ... ,.,., ,..,,.... iv
LIST OF ILLUSTRATIONS . ,. . . . . , , ,9 . .99of, , 0 v
Thesis
Introduction 9 . 9 9 9 9 . , 9 , , , 9 , , , * . 9 1
Method.......... . . , . . 9 , , 9 , , , . 9
SubjectsApparatusProcedure
SurgeryBrain Stimulation
Results , . 9 9 9 9 . 9 9 . 9 . 9 . 9 9 9 . 9 . , . 13
Discussion . . . ,V . . . , , . , , . . . . . . 16
References . . . . . . . . . , , , . , . . 21
iii1
LIST OF TABLES
1. Summary Table of the ANOVA of DifferenceScores 15
iv
Table Page
LIST OF ILLUSTRATIONS
Figure Page
1. Mean Difference Scores from Baseline as aFunction of Time Since HypothalamicStimulation . . . , , , , , .
0 1 g0 p 0 0 p p p p 14
v
THE EFFECT OF HYPOTHALAMIC STIMULATION
ON THE PHAGOCYTIC ACTIVITY OF THE
RETICULOENDOTHELIAL SYSTEM
For many years "psychological stress" has been known to
affect disease resistance, and more recently has been hypoth-
esized to play a major role in life-threatening conditions
heretofore not within the domain of psychosomatic medicine
(Solomon & Amkraut, 1972; Stern, Mickey, & Gorski, 1969).
This relationship seemed to imply involvement of the central
nervous system in immunity, but comprehensive research eluci-
dating specific brain mechanisms has yet to be performed,
However, the brain structure most critically implicated in
integrating the organism's response to deviations from
homeostasis was shown to be the hypothalamus, and thus this
structure appeared likely to be involved in altering the
immune response.
Recently, several studies have established a relation-
ship between the hypothalamus and functioning of the immune
system. For instance, lesions of the posterior hypothalamus
prevented the formation of antibodies in response to a sec-
ondary antigenic challenge, and lesions in the anterior or
medial hypothalamus produced a depressed hypersensitive
reaction to picryl chloride accompanied by lowered levels of
antibodies (Macris, Schiavi, Camerino, & Stein, 1970).
1
2
Posterior hypothalamic lesions in rats have also been shown
to alter the morphological characteristics of the primary
immune response as indicated by depressed antibody synthesis
and a reduced number of antibody-producing cells (Kishkovaskya,
Zufarov, Saakov, & Polyak, 1974). This reduction in effici-
ency of the immune response following posterior hypothalamic
lesions was supported by the demonstration that allergic
polyneuritis reactions were accentuated by posterior hypothal-
amic lesions in rabbits (Konovalov, Korneva, & Khai, 1971).
Clinically relevant results were shown following anterior
hypothalamic lesions which reduced susceptibility to
increases in tumor growth and anaphylactic shock (Kavetsky,
Turkevich, Akimova, Khayetsky, & Matuechuck, 1969; Schavi,
Adams, & Stein, 1966). Besedovsky and Sorkin (1977) demon-
strated that neuronal activity increased in medial hypothal-
amic areas simultaneously with IgM antibody systhesis in the
spleen, but these results were difficult to interpret because
the possibility of general activation of neural circuitry via
antibody synthesis was not assessed.
Significant deviations in the immune response were also
demonstrated following lesions or electrical stimulation of
other hypothalamic nuclei. For example, dorsal hypothalamic
lesioned animals had lowered antibody titers (Korneva & Khai,
1963). Fessel and Forsyth (1963) also found that lateral
hypothalamic stimulation increased gamma globulin levels in
the bloodstream.
3
Results have not invariably indicated involvement of the
hypothalamus in the immune system. For example, Thrasher,
Bernadis, and Cohen (1971) found that neither anterior,
medial, nor posterior hypothalamic lesions affected antibody
levels comparable to that of intact controls. In addition,
Ado and Goldstein (1973) reported that rabbits receiving
lesions in the anterior, medial, or posterior hypothalamic
areas showed no significant increase or decrease in binding
antibodies, However, the majority of investigations have
concluded that the hypothalamus may be involved in immune
responses although the underlying mechanisms have remained
unknown.
In attempting to determine the role of hypothalamic
mechanisms in immunity, investigators have consistently over-
looked a major component of the immune response known as the
reticuloendothelial system. Research demonstrated that the
reticuloendothelial system removed toxins, injured cells,
bacteria, and other foreign substances from the bloodstream
by a process of engulfment termed phagocytosis (Carr, 1973).
The reticuloendothelial system has also been shown to be
responsible for the activation of gamma globulin formation
which was the variable assessed by most previous studies.
Specifically, the cells which comprise this system have been
termed macrophages (Carr, 1973).
Macrophages have been classified into two major types of
cells labeled fixed or free phagocytes. Fixed phagocytes
4
were found embedded within the sinusodial linings of the
liver, spleen, adrenal glands, lymph nodes, and bone marrow,
while free macrophages were found in the lymphatic fluid and
within the bloodstream in the form of leukocytes (Bailiff,
196Q) . The process of phagocytosis performed by both fixed
and free phagocytes has been shown to occur in three distinct
stages initiated by a chemical reaction produced by the invad-
ing substance. This reaction, called chemotaxis, enabled the
phagocytes to move toward or away from the substance in ques-
tion (Carr, 1973). 'The first stage of phagocytosis has been
termed attachment and may involve specific receptors on the
macrophage cellular membrane which have a high affinity for
particular antigens. The second stage has been called inges-
tion and is believed to entail the engulfment of foreign
particles by finger-like processes which extend into the
bloodstream and trap foreign matter. The third stage of
phagocytosis, digestion, has been thought to be a process
whereby the engulfed particle is broken down through a chemi-
cal reaction by enzymes within the macrophage.
In addition to phagocytosis, macrophages were shown to
interact with other important components of the immune system
(Carr, 1973). For example, Nakano and Muramatsu (1976) showed
that animals injected with macrophage-bound bovine serum
albumin resulted in an enhanced response to a secondary anti-
genic challenge. Macrophages have also been implicated in
the transport of antigens to lymph cells for antibody
5
production as well as synthesizing antibodies themselves
(Carr, 1973; Friedman, 1960; Wissler, 1960). In addition, a
class of antibodies called opsonins have been shown to be
important in the preparation of antigenic materials for phago-
cytosis (Frobisher, Hindsill, Crabtree, Goodhart, & Gordon,
1974).
The response of the reticuloendothelial system to stress,
endocrine substances, endotoxins, and neoplastic growth has
also been investigated by a number of researchers (Old,
Clarke, Benacerraf, & Goldsmith, 1960; Park & Scarborough,
1972; Reichard, 1972; Stowe, 1977; Zweifach, 1960). For
example, Old et al. (1960) found that reticuloendothelial
system activity was heightened 5 days following a challenge
with sarcoma 180 cells, but that progressive growth of the
tumor resulted in a diminished rate of reticuloendothelial
system activity. Electric shock administered to rats
resulted in a degeneration of the phagocytic cells of the
liver and spleen along with a depression in reticuloendothe-
lial activity (Zweifach, 1960). Stowe (1977) found that rats
receiving zymosan, a chemical agent which stimulates reticulo-
endothelial activity, resulted in poorer performance on a
Sidman avoidance task than did nonstimulated controls.
Reichard, Gordon, and Tessmer (1960) found that blockade of
the reticuloendothelial system increased the susceptability
of rats to traumatic shock and eliminated acquired resistance
to shock produced by repetitive exposures to sublethal doses
6
of the stressor. Extracts from the spleen and liver of rats
that were previously trained to resist trauma protected naive
controls against the lethal effects of tumbling in a drum
apparatus (Reichard, 1972). Furthermore, these extracts pro-
tected naive subjects from S. typhosa endotoxin. In a condi-
tioned suppression paradigm, reticuloendothelial stimulation
resulted in an increased rate of responding during the pre-
sentation of a conditioned stimulus that had been previously
paired with shock, and the authors proposed that reticuloen-
dothelial activity affected a nonspecific defense mechanism
against stress or psychological trauma (Park & Scarborough,
1972).
Alterations in the reticuloendothelial system during
stress were demonstrated to correlate with changes in endo-
crine activity (Bailiff, 1960; Bilder, 1976; DiLuzio, 1960;
Keefe, Helman, & Smith, 1967; Timeras & Selye, 1949; Zweifach,
1960). Adrenal hypertrophy has been shown to accompany
reticuloendothelial activation in response to shock, and fol-
lowing adrenalectomy, animals showed a decreased responsivity
in the reticuloendothelial system (Zweifach, 196Q). Zweifach
suggested that adrenal corticotropic hormone which stimulated
the adrenal glands to secrete corticosterone was necessary
for a normal reticuloendothelial response to stress. Hypo-
physectomized rats resulted in a decreased phagocytic capacity
of the reticuloendothelial system as well as decreased weight
of liver, spleen, and lungs. Although hypophysectomy
7
decreased phagocytic activity, there was no dimunition in
reticuloendothelial responsivity to the stimulating agent
zymosan. The authors attributed the reduction of the phago-
cytic index following hypophysectomy to a reduction in mass
of reticuloendothelial system organs and to decreased blood
volume (Keefe et al., 1967). Bilder (1976) showed that adre-
nalectomy alone followed by replacement of exogenous cortisone
had no effect on reticuloendothelial activity. However, both
thyroidectomy or hypophysectomy resulted in a decrement in
reticuloendothelial system clearance rates. Also, other
measures of immune responsiveness such as antibody synthesis
have been shown to be altered by exposure to stressful condi-
tions resulting in changes in the organism's ability to
resist disease (Corson, 1966; Jenson & Rasmussen, 1963;
LaBarba, 1970; Rashkis, 1952; Solomon & Amkraut, 1972; Vessey,
1964).
Unlike other aspects of the immune response, the role of
hypothalamic mechanisms on reticuloendothelial system activ-
ity has been largely ignored, and because the reticuloendo-
thelial system has been implicated in participation with
immune mechanisms responsible for antibody production, the
possibility exists that the hypothalamus or other central
nervous system structures could influence reticuloendothelial
activity. Segal, Izak, and Feldman (1971) electrically stim-
ulated the posterior hypothalamus in rats and found that
prolonged stimulation resulted in decreased hemoglobin
8
concentrations, hyperplasia of bone marrow, spleen, and
liver cells, along with increased red cell destruction.
These authors concluded that the reticuloendothelial hyper-
plasia resulted from the increased production of red blood
cells. Shekoyan, Khasman, and Uchitel (1975) found that
bilateral electrolytic coagulation of the posterior and
supraoptic nuclei of rabbit hypothalami had little effect on
the ability of macrophages to engulf sheep red blood cells,
but that supraoptic damage increased india ink clearance at
all periods of measurement.
If the central nervous system were responsible for
influencing the activity of the reticuloendothelial system,
then the most likely area involved would be the hypothalamus
because this structure has been shown to alter other aspects
of immunoresponsivity. Also, the hypothalamus has been
demonstrated as the focus for central nervous system control
over endocrine and autonomic functions that interact with
immune mechanisms.
The purpose of this experiment was to investigate the
effect of medial hypothalamic stimulation on the activity of
the reticuloendothelial system. Specifically, it was hypoth-
esized that medial hypothalamic stimulation would change
reticuloendothelial activity as measured by the rate of car-
bon clearance from the bloodstream. The medial hypothalamus
was chosen for the site of stimulation because of its inte-
gral involvement in the maintenance of homeostatic mechanisms
essential for the survival of the organism,
9
Method
Subjects
Subjects were eight experimentally naive male albino
250 gram Sprague-Dawley rats (ARS Sprague-Dawley, Madison,
Wisconsin). Each animal was individually housed and allowed
food and water ad-libitum throughout the experiment.
Upon arrival each animal was observed for any signs of
respiratory infection and if such an infection was observed,
a dose of .2 cc penicillin was administered intramuscularly
daily for a period not exceeding 5 days. No animal was sub-
jected to clearance testing unless a minimum of 3 days passed
since the last administration of the antibiotic.
Apparatus
During intracranial stimulation, subjects were placed in
a Lehigh Valley operant chamber with a hole in the ceiling to
permit passage of a shielded cable. The chamber was 28.58 cm
X 21.59 cm X 21.59 cm (Lehigh Valley Electronics, Beltsville,
Maryland). The floor consisted of stainless steel bars
spaced 1.27 cm apart, and the walls and ceiling of the cham-
ber were constructed of clear plexiglass.
Brain stimulation was delivered by a Grass S48 brain
stimulator (Grass Instruments, Quincy, Massachusetts). A
bifurcated shielded cable 120 cm in length with a stainless
steel spring covering (50 cm in length) and two Plastic
Products #303 electrode plugs were used to deliver brain
stimulation (Plastic Products, Roanoke, Virginia).
10
A Kopf stereotaxic apparatus (Kopf Instruments, Tujunga,
California) was used in the surgical implantation of elec-
trodes. The electrodes were MS/303 stainless steel, 32 mm in
length and .15 mm in diameter. Self-tapping stainless steel
mounting screws .16 mm in length along with cranioplastic
liquid and powder were utilized in the permanent fixing of
the implanted electrodes. All electrodes, mounting screws,
and cement were supplied by Plastic Products, Inc., Roanoke,
Virginia.
A Bausch and Lomb Spectronic 20 Spectrophotometer with
a wavelength range of from 340 nm to 950 nm was used to
determine clearance rates of blood samples (Bausch & Lomb,
Rochester, New York).
Procedure
Surgery. Animals were first implanted with polyethel-
ene cannulas constructed according to a modification of the
method outlined by Weeks (1967). Animals were anesthetized
with sodium pentobarbitol at a dose of 50 mg per kilogram,
Following anesthesia, the polyethelene cannula was implanted
in the right jugular vein utilizing the procedure described
by Weeks (1967). After 4 days recovery from the above pro-
cedure, each animal was placed in a stereotaxic apparatus
and the skull was exposed by incision approximately 1 inch
long. Following the incision, the skull was trephined and
electrodes were implanted bilaterally in the ventromedial
area of the hypothalamus. The stereotaxic coordinates for
11
the implantation of the electrodes were as follows: 6.7 mm
anterior of the interaural line, .75 mm lateral of the mid-
saggital sinus, and 9.5 mm ventral from the dural surface of
the brain (Sherwood & Timeras, 1970).
Following the return of each animal to his preoperative
weight, subjects were removed from their home cates and a
colloidal suspension of carbon particles (Koh-I-Nor Rapido-
graph, Inc., Bloomsbury, New Jersey) was prepared. The col-
loidal suspension was mixed in a ratio of 1:3 with .9%
physiological saline resulting in a concentration of 25mg/ml.
Each animal was injected with this mixture through the jugu-
lar cannula at a ratio of 5 mg/kg of body weight, Prior to
the administration of the suspension, the tail of each animal
was clipped and a .25 ml blood sample was taken from the tail
vein by a "milking" procedure. This first blood sample
served as a baseline measure. Following this procedure, the
carbon suspension was injected into the jugular cannula in
the ratio outlined above and .025 ml aliquots of tail vein
blood were taken at 1-minute intervals for 15 minutes, All
blood samples were lysed in a 4 ml .1% solution of sodium
carbonate (Na2CO3 ). The sodium carbonate solution was a mix-
ture of 1 gm of Na2CO3 to one liter of deionized water. The
samples were next subjected to spectrophotometric analysis
at a setting of 675 nm. Each blood sample was read against
a blank of 4 ml of .1% Na2 CO3 , Optical densities were cal-
culated by subtracting the absorbance value of the baseline
12
blood sample from each of the 15 1-minute blood samples taken
after the injection of the carbon suspension, The logarithms
of these optical densities and half-time clearance rates were
calculated for each animal from the slope of the regression
line by means of the formula T = b (Stowe, 1977), where
.301 is the logarithm of 2 and b is the slope of the regres-
sion line based on a least-squares regression equation util-
izing the logarithms of the optical densities across time.
Brain stimulation. Following the determination of the
carbon clearance rates for each animal after the surgical
procedures, a period of 5 days lapsed before the next phase
of the experiment began. At the end of this period, each
animal was placed in the operant chamber where intracranial
brain stimulation was delivered by a Grass S48 brain stimu-
lator through a bifurcated cable. Each animal received 1
train of rectangular wave form pulses every 5 seconds up to
a maximum of 6 volts, with the duration of each train lasting
1 second. The intensity of brain stimulation was adjusted
for each animal by beginning the first session at 1 volt and
moving up in 1-volt increments every 2 minutes until either
the maximum of 6 volts was reached or until an aversive reac-
tion to brain stimulation was observed. If an aversive
reaction was observed, the intensity was lowered by 1 volt
and this parameter was held constant for each animal through-
out the experiment. An aversive reaction was defined as
vocalization or exaggerated motor behavior at the onset of a
13
stimulus pulse. Each train of stimulation delivered 100 stim-
ulus pulses per second with the duration of each stimulus
pulse lasting .2 msec. After 2 hours of brain stimulation,
each animal was returned to his home cage for a period of
96 hours. At the end of this period, each animal was sub-
jected to another carbon clearance test. This measurement
was used to assess any long-term effects of brain stimulation.
After 4 days, each animal received intracranial stimulation
using the parameters outlined above and measured using the
carbon clearance test 3, 6, 12, and 24 hours post-brain
stimulation in a counterbalanced sequence. A 4-day period
was imposed between each measurement to allow for carry-over
effects.
Results
Results presented in Figure 1 indicate that ventromedial
hypothalamic stimulation decreases the rate of carbon clear-
ance from the bloodstream. The points along the abcissa
represent the poststimulation measurement periods. The ordi-
nate represents mean difference scores from baseline. The
difference scores were obtained by subtracting the mean half-
time clearance rates for each poststimulation period from
the average half-time carbon clearance rate at baseline. The
half-time carbon clearance rate indicates the amount of time
in minutes taken to clear half of the injected carbon. A
one-way repeated ANOVA of difference scores shows a signifi-
cant overall effect (F = 5.47, p < .01). The summary of
14
3.0-
2 .5-
2.0-
1.5-Q)-P
1.0-
0.5-0
00
4, -0. 5-
a)44
-2.0-
-2.5-
3 6 12 24 96
Poststimulation Periods/Hours
Figure 1. Mean difference scores from baseline as a functionof time since hypothalamic stimulation. Negativescores indicate slower carbon clearance ratesrelative to baseline.
15
this analysis is shown in Table 1. A check on the assumption
of compound symmetry of the variance-covariance matrix yields
the parameter 0 = .66. The resulting degrees of freedom are
(k-l) 6 = 3 for the numerator, and (k-1) (n-1) 0 = 19 for the
denominator. The significance level of the obtained F did
not change following the correction for degrees of freedom.
By Newman-Keuls post hoc analysis of the difference scores
the 3-, 6-, 12-, and 24-hour poststimulation periods do not
differ from each other but show a significant increase from
the 4-day measure.
Table 1
Summary Table of the ANOVA of Difference Scores
Source of Variation SS df MS F
Between 282.14 7
Within 115.81 32
Measurement periods 50.82 4 12.71 5,47*
Residual 64.99 28 2.32
Total 397.95 39
*p < .01.
The form of the relationship between brain stimulation
and half-time clearance rates appears to be curvilinear. A
significant quadratic trend supports this observation (F =
11.42, p < .01). In addition, six of the eight subjects
16
showed U-shaped functions when individual curves were
plotted.
The results of histological examination reveal that the
electrodes were generally in the VMN with no indication of
lesion at the tip. There appeared to be a correlation
between electrode placement and changes in reticuloendothel-
ial activity. The six subjects showing distinctive U-shape
functions had electrodes in the VMN adjacent to the third
ventricle, while the other two subjects had one electrode
on the lateral border of the medial hypothalamus,
Discussion
Results of this investigation suggest that central ner-
vous system activity may have an effect on the reticuloendo-
thelial system by depressing macrophage function. This is
consistent with studies reporting effects on other measures
of immune system activity. In this study, carbon clearance
rates are depressed for at least 24 hours poststimulation.
The effect is present at 3 hours, reaches a peak at 12 hours,
is decreasing at 24 hours, and by 96 hours returns to base-
line.
The present experiment should be considered a prelimi-
nary attempt to determine whether measurable changes in
reticuloendothelial activity can be produced by brain stimu-
lation. Because of the nonphysiological amount of stimula-
tion, the pattern of results observed here is not necessarily
indicative of changes following central nervous system
17
activation in the intact animal. In fact, stimulation rather
than depression of reticuloendothelial activity seems possi-
ble because stimulation can increase or decrease other mea-
sures of immune system activity such as gamma globulin
formation (Fessel & Forsyth, 1963; Korneva & Khai, 1963).
Also, synthesis of particular antibodies in organ systems in
which reticuloendothelial activity occurs results in an
increase in neural activity (Besedovsky & Sorkin, 1977). In
addition, sympathetic arousal is known to be produced by
hypothalamic stimulation (Panksepp, 1971), and sympathetic
arousal also leads to an increase in adrenal output which
parallels reticuloendothelial activation (Zweifach, 1960).
The effects observed in this study may be a result of
stimulating neural pathways which produce endocrine secre-
tion, autonomic changes, or direct immunodepression by
unknown mechanisms. Some alternative explanations to the
above interpretation include blood pressure changes, vascular
changes, or prolonged neural afterdischarge. The time course
of the present results does not appear to be consistent with
these explanations. Any of these alternative effects should
not persist for 24 hours and would not be expected to increase
until 12 hours poststimulation.
Diurnal variation in reticuloendothelial activity is an
alternative explanation that does appear to be consistent
with the time course observed, particularly because the 12-
hour measurement shows the greatest decrease in carbon
18
clearance rate. However, the 96-hour measurement is differ-
ent statistically from the 3- and 24-hour measurements, but
these three measurements were taken at approximately the same
time of day. Also, the 6-hour and 12-hour measurements are
very close in clearance rates, but the 6-hour measurement was
taken in the early afternoon, while the 12-hour measurement
was taken late in the evening.
Although the alternative explanations mentioned above
cannot be ruled out, they do not seem to adequately explain
these findings. Thus, the present results do suggest that
immunoresponsivity is under direct central nervous system
control via caudal influences by fiber systems which either
originate in or course through hypothalamic areas. The
results also indicate that these pathways can decrease phago-
cytic activity in the reticuloendothelial system which oper-
ates in conjunction with other parts of the immune system to
provide resistance against invading organisms. The precise
way in which reticuloendothelial system activity interacts
with antibody production is unknown, yet based on the present
results and previous studies on antibody formation, both are
influenced by hypothalamic mechanisms. Therefore research
on the relationship between the immune system and the hypo-
thalamus should assess changes in both antibody formation
and reticuloendothelial system activity concurrently.
Future research should also attempt to replicate these
findings using different electrode placements and stimulation
19
parameters. One possibility would be to determine the
effects of stimulation on the immune response of stressed
subjects or subjects exposed to immune-activating substances.
Brain stimulation should alter the response of subjects to
invasion by reticuloendothelial-stimulating material. For
example, the reticuloendothelial system is intimately involved
in the reaction to neoplastic growth (Old et al., 1960), thus
brain stimulation may alter tumor growth. Continued research
on the neurophysiological mechanisms involved in the immune
response should be explored so as to increase our understand-
ing of the organism's ability to resist disease.
The far-reaching implications of these data have poten-
tial importance for our understanding of the functioning of
immune systems in the intact organism in its environemnt.
The hypothalamus participates in a variety of functions impor-
tant to survival and the maintenance of homeostasis. For
example, the hypothalamus is known to control many aspects of
metabolism and Powley (1977) in a comprehensive review summar-
izes evidence that this control is modified by conditioning.
The possibility exists that hypothalamic control of the immune
system is also altered by conditioning. The demonstration
that conditioning of the immune system occurs using a
Pavlovian classical procedure is consistent with this specu-
lation (Adler & Cohen, 1975; Rogers, Reich, Storm, & Carpenter,
1976). Specifically, these studies demonstrate that rats
receiving pairings of saccharine and an immunosuppressive
20
agent, cyclophosphamide, show a decrease in antibody titers
when presented with saccharine alone. This demonstration
strengthens the possibility that the immune system is modi-
fiable through environmental conditioning. Taken together
with research on hypothalamic structures in immune processes,
metabolic adjustments, and concomittant changes in the moti-
vational state of the organism, a common neural mechanism
through which changes in immunoresponsivity as a function of
environmental conditions may underlie the complex relation-
ships observed in the realm of psychosomatic illness.
21
References
Adler, R., & Cohen, N. Behaviorally conditioned immunosup-
pression. Psychosomatic Medicine, 1975, 37(4), 333-340.
Ado, A. , & Goldstein, M. The primary immune response in
rabbits after lesion of the different zones in the medial
hypothalamus. Annals of Allergy, 1973, 31, 585-589.
Bailiff, R. N. Reaction patterns of the reticuloendothelial
system under stimulation. Annals of the New York Academy
of Sciences, 1960, 88(1), 3-13.
Besedovsky, H., & Sorkin, E. Network of immune-endocrine
interactions. Journal of Clinical Experimental Immunology,
1977, 27, 1-12,
Bilder, G. E. Activity of the reticuloendothelial system
following endocrine manipulation in rats. Journal of the
Reticuloendothelial Society, 1976, 19, 11-17.
Carr, I. The Macrophage: A review of ultrastructure and
function. New York: Academic Press, 1973.
Corson, S. A. Neuroendocrine and behavioral response patterns
to psychologic stress and the problem of the target tissue
in cerebrovisceral pathology. Annals of the New York
Academy of Sciences, 1966, 125, 890-918.
DiLuzio, N. R. Reticuloendothelial involvement in lipid
metabolism. Annals of the New York Academy of Sciences,
1960., 88(2) , 244-251.
Fessel, W. J. , & Forsyth, R. Hypothalamic role in control of
gamma globulin levels. Archives of Allergy, 1963, 771.
(Abstract)
22
Freidman, H. H. Reticuloendothelial system and passive trans-
fer of endotoxin tolerance. Annals of the New York Academy
of Sciences, 1960, 88(1) , 99-106.
Frobisher, M., Hindsill, R., Crabtree, K., & Goodhart, C.
Fundamentals of microbiology. Philadelphia: W. B.
Saunders, 1974.
Jenson, M. M., & Rasmussen, A. F., Jr. Stress and suscepti-
bility to vesicular stomatitis virus. Journal of Immunol-
ogy, 1963, 90, 21-23.
Kavetsky, R., Turkevich, N., Akimova, R., Khayetsky, I., &
Matuechuck, Y. Induced carcinogenisis under various
influences on the hypothalamus. Annals of the New York
Academy of Sciences, 1969, 164(2), 517-519,
Keefe, B., Helman, S., & Smith, J. J. RES response to hypo-
physectomy in the rat. Journal of the Reticuloendothelial
Society, 1967, 4, 177-189.
Kishkovaskaya, A., Zufarov, A., Saakov, B., & Ployk, A.
Morphological and submicroscopic characteristics of the
primary immunologic response after destruction of the
posterior hypothalamic nuclei. Bulletin of Experimental
Biology and Medicine, 1974, 79, 78-83,
Konovalov, G., Korneva, F., & Khai, L. Effect of destruction
of the posterior hypothalamic area on the experimental
allergic polyneuritis. Brain Research, 1971, 29, 383-386.
Korneva, F., & Khai, L. Effect of destruction of hypothala-
mic areas on immunogenesis. Fiziol. Sechenov, 1963, 49,
42.
23
LaBarba, R. Experimental and environmental factors in cancer:
A review of the research with animals. Psychosomatic Med-
icine, 1970, 32, 359-372.
Macris, N. T., Schiavi, R., Camerino, M., & Stein, M. Effect
of hypothalamic lesion on the immune process in the guinea
pig. American Journal of Physiology, 1970,, 19, 1205-1209.
Nakano, K., & Muramatsu, S. Studies of the role of macro-
phages in the antibody response of mice. Stimulation of
T-cell dependent antibody responses by tolerogenic soluble
antigen trapped by macrophages. Journal of the Reticulo-
endothelial Society, 1976, 19, 347-359.
Old, L., Clarke, D., Benacerraf, A., & Goldsmith, M. The
reticuloendothelial system and the neoplastic process.
Annals of the New York Academy of Sciences, 1960, 88(2),
264-280.
Panksepp, J. Aggression elicited by electrical stimulation
of the hypothalamus in albino rats. Physiology and Behav-
ior, 1971, 6, 321-329.
Park, L., & Scarborough, B. Reticuloendothelial stimulation
and depression: Effects on conditioned suppression.
Journal of the Reticuloendothelial Society, 1972, 12, 629-
639.
Powley, T. L. The ventromedial hypothalamic syndrome, satiety
and a cephalic phase hypothesis. Psychological Review,
19 77,, 84 (1)1, 89-126.
Rashkis, H. Systematic stress as an inhibitor of experimental
tumors in Swiss mice. Science, 1952, 116, 169.
24
Reichard, S. RES stimulation and transfer of protection
against shock. Journal of the Reticuloendothelial Society,
1972, 12, 604-617.
Reichard, S., Gordon, A., & Tessmer, C. Humoral modification
of the function of reticuloendothelial system. Annals of
the New York Academy of Sciences, 1960, 88(l) , 213-231.
Rogers, M. P., Reich, P., Strom, T. B.., & Carpenter, C. B,
Behaviorally conditioned immunosuppression: Replication
of a recent study. Psychosomatic Medicine, 1976, 38(6),
447-451.
Schaivi, R., Adams, J., & Stein, M. Effect of hypothalamic
lesions on histamine toxicity in the guinea pig. American
Journal of Physiology, 1966, 211, 1269-1273.
Segal, R., Izak, G., & Feldman, S. Augmented red cell seques-
tration after prolonged electrical stimulation of the
posterior hypothalamus in rats. Journal of the Reticulo-
endothelial Society, 1971, 9, 225-236.
Shekoyan, V., Khasman, E., & Uchitel, I. The effect of
structures of the anterior and posterior hypothalamus on
the engulfment and digestion of the antigen by macrophages
and the India ink clearance. Journal of Microbiology and
Epidemiology, 1975, 10(3), 131-135.
Sherwood, N. M., & Timiras, P. S. A stereotaxic atlas of
the developing rat brain. Berkeley, California: University
of California Press, 1970.
Solomon, G., & Amkraut, A. Emotions, stress and immunity.
Frontiers of Radiation Therapy, 1972, 7, 84-96.
25
Stern, E., Mickey, M. R., & Gorski, R. A. Neuroendocrine
factors in experimental carcinogenisis. Annals of the
New York Academy of Sciences, 1969, 164(2),, 494-507.
Stowe, J. E. The effects of stimulation and depression of
the reticuloendothelial system on Sidman avoidance behav-
ior (Doctoral dissertation, North Texas State University,
1977). Dissertation Abstracts International, 1977, 38,
1460. (University Microfilms No. 77-19685)
Thrasher, S., Bernadis, L., & Cohen, S. The immune response
in hypothalamic lesioned and hypophysectomized rats.
International Archives of Allergy and Applied Immunology,
1971, 41, 813-820.
Timeras, P. S., & Selye, H. On the participation of the
reticuloendothelial system on the alarm reaction. Science,
1949, 110, 560-561.
Vessey, S. Effects of grouping on levels of circulating anti-
bodies in mice. Proceedings of Society of Experimental
Biological Medicine, 1964, 115, 252-255.
Weeks, J. R. Cardiovascular techniques using unanesthetized
and freely moving rats. Unpublished manuscript, Upjohn
Co., Kalamazoo, Michigan, 1967.
Wissler, R. W., Fitch, F. W., & LaVia, M. F. The reticulo-
endothelial system in antibody formation. Annals of the
New York Academy of Sciences, 1969, 88(2), 134-147.
Zweifach, B. W. The contribution of the reticuloendothelial
system to the development of tolerance to experimental
26
shock. Annals of the New York Academy of Sciences, 1960,
88(2), 203-212.
