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Systemic epinephrine and defensive burying in the rat Terlecki, Lori Janine 1981

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SYSTEMIC EPINEPHRINE AND DEFENSIVE BURYING IN THE RAT by LORI JANINE TERLECKI B.Sc. The University of Calgary, 1975 M.Sc. The University of Calgary, 1977 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES Department of Psychology We accept this thesis as conforming to the required standard THE UNIVERSITY OF March © Lori Janine BRITISH COLUMBIA 1981 Terlecki, 1981 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of ~P~3 y c H o L n a c/ The University of British Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date MAILC.H ao /•?*•/ i i ABSTRACT Many investigators have suggested that epinephrine influences the behaviour of organisms in aversive situations; however, attempts to confirm this prediction by examining the effects of adrenal demedullation and epinephrine injections on the performance of rats in traditional aversive conditioning paradigms have failed to provide unambiguous support for this point of view. In the present investigations, the recently developed defensive burying paradigm was used to assess the effects of epinephrine on the behaviour of rats in aversive situations. Defensive burying refers to the fact that rats typically respond to well-defined aversive objects by pushing moveable material towards and over them. Rats with demedullated adrenal glands, and therefore reduced systemic levels of epinephrine, exhibited reduced levels of burying of an unconditioned aversive stimulus (Experiments 5 and 6). This reduction of burying observed in demedullated rats was counteracted by replacement injections of epinephrine (Experiment 6). Intact rats given systemic injections of .01, .1, .5 or 1 mg/kg of epinephrine exhibited increased levels of burying of both unconditioned and conditioned aversive stimuli (Experiments 1, 2, 3, 4, and 6); whereas, a larger dose (2 mg/kg) of epinephrine produced an obvious motor impairment (Experiment 4). These findings clearly confirm the hypothesis of a relation between levels of epinephrine and the responsiveness of organisms to aversive stimulation. Furthermore, the systematic and robust nature of these results illustrates the utility of iii the defensive burying paradigm in the investigation of epinephrine-behaviour relations and the mechanisms that underlie them. iv TABLE OF CONTENTS ABSTRACT ii LIST OF TABLES viLIST OF FIGURES viiACKNOWLEDGMENT ix INRODUCTION 1 EPINEPHRINE AND AVERSIVE RESPONDING IN RATS 2 The Effects of Epinephrine AdministrationThe Effects of Epinephrine Depletion 7 EVALUATION OF STUDIES EXAMINING THE RELATIONSHIP BETWEEN EPINEPHRINE AND AVERSIVE RESPONDING 7 GENERAL PURPOSE 12 Defensive BuryingGeneral Description of Defensive Burying 12 Defensive Burying and Epinephrine 14 PURPOSE 17 GENERAL METHODS 18 SubjectsApparatusGeneral Procedures 19 HabituationBehavioural Observation and Quantification 19 EFFECT OF EXOGENOUS EPINEPHRINE ON DEFENSIVE BURYING 19 Experiment 1Method 20 Results and Discussion 22 Experiment 2 5 Method 6 V Results and Discussion 26 Experiment 3 0 MethodResults and Discussion 31 Experiment 4 3Method 4 Results and Discussion 3EFFECT OF DEMEDULLATION ON DEFENSIVE BURYING 38 Adrenal Anatomy .* 39 Adrenal Demedullation 3Experiment 5 40 MethodSurgeryBehavioural testing 42 Histology 4Results and Discussion 42 Experiment 6 5 Method . 45 Results and Discussion 46 GENERAL DISCUSSION 49 Accomplishments of the Present Studies 50 Evidence for a Behavioural Effect of Epinephrine 5Evidence Concerning the Nature of the Relationship Between Epinephrine and Aversive Responding 51 Reasons for the Popularity of Conditioned Active Avoidance Paradigms 53 vi Effect of Epinephrine Injections on Human Behaviour 54 Mowrer's Theory of Avoidance Conditioning 56 Why Active Avoidance Paradigms Have Not Been Successful 57 Conclusion 8 REFERENCES 60 vii LIST OF TABLES Table 1. Effects of Epinephrine Administration on Aversive Responding 3 Table 2. Effects of Adrenal Demedullation on Aversive Responding 8 vi i i LIST OF FIGURES Figure 1. Mean duration of burying and mean final height of bedding material at the dowel on 4 testing days for rats injected with epinephrine and rats injected with saline 23 Figure 2. Mean duration of burying and mean final height of bedding material at the flashbulb on 4 testing days for rats injected with epinephrine and rats injected with saline 27 Figure 3. Mean duration of burying and mean final height of bedding material at the trap on 4 testing days for rats injected with epinephrine and rats injected with saline 32 Figure 4. Mean duration Of burying and mean final height of bedding material at the dowel for rats injected with one of five different doses of epinephrine 35 Figure 5. Mean duration of burying and mean final height of bedding material at the trap for rats that had their adrenal glands demedullated and rats that had "sham" operations. 43 Figure 6. Mean duration of burying and mean final height of bedding material at the trap for demedullated and "sham" control rats injected with one of three different doses of epinephrine 47 ix ACKNOWLEDGEMENT The author wishes to thank her supervisor Dr. John P.J. Pinel for the assistance and guidance he provided during the research for and preparation of this dissertation. The author would also like to express her gratitude to the remaining members of her supervisory committee, Dr. B. Gorzalka and Dr. R. Corteen for their recommendations and encouragement. Special thanks are extended to Marcia Spetch and Dallas Treit for their invaluable aid and support, as colleagues and as friends. Sincere appreciation is expressed to G. Renfrey for his assistance with the preparation of the figures included in this dissertation. Finally the author is indebted to Dr. D. Shaun Gray for his patience, suggestions, and invaluable encouragement during her entire Ph.D. program. 1 INTRODUCTION Since the observation by Cannon and de la Paz (1911) that the hormone epinephrine was released from the adrenal glands of a cat "frightened" by a barking dog, many studies have confirmed that the adrenal medulla of humans and other animals secretes epinephrine in response to aversive stimulation (Frankenhaeuser, 1971; Mason, 1968; Smith, 1973). For example, increased epinephrine output from the adrenal medulla has been found to occur in response to electric shock (McCarty & Kopin, 1979), radial acceleration (Goodall, 1962), and dental treatment (Schmidt, Suss, Zicha, Suss, & Weiss, 1964). This consistent relationship between aversive stimulation and the elevation of circulating epinephrine levels prompted some investigators (e.g., Latane & Schachter, 1962; Levine & Soliday, 1962) to predict that epinephrine might actually cause or at least enhance the changes in affect and behaviour that occur in aversive situations (Leshner, 1978). This prediction has been confirmed by a few experiments. For example, systemic administration of epinephrine has been found to enhance two-way active avoidance responding in rats (Latane' & Schachter, 1962); trembling, urination, and defecation in rats exposed to a flashing light and loud noise (Singer, 1963); and anger-related behaviour in humans (Schachter & Singer, 1962). One of the most interesting aspects of the ability of systemically injected epinephrine to enhance responding in aversive situations is that epinephrine does not penetrate the blood-brain barrier in appreciable amounts (Weil-Malherbe, Axelrod, & Tomchick, 1959). Although a number of potential 2 mechanisms have been proposed, the means by which epinephrine affects the central nervous system and consequently produces behavioural changes is still unknown (Gold, van Buskirk, & Haycock, 1977; McCarty & Kopin, 1979). Identification of this mechanism has been hampered by the fact that the effects of peripheral epinephrine on behaviour in aversive situations have not been consistent from experiment to experiment (Smith, 1973). In the following sections, the literature concerning the relationship between systeic epinephrine and "aversive responding" in rats will be reviewed and evaluated. Because so few relevant studies have been conducted on subjects other than the laboratory rat, their discussion is omitted here. The relevant studies performed on humans are briefly reviewed in the General Discussion. EPINEPHRINE AND AVERSIVE RESPONDING IN RATS The relationship between epinephrine and aversive responding has been investigated by altering circulating epinephrine levels and observing the effects of this alteration on behaviour in aversive situations. There are two ways in which systemic epinephrine levels have been altered: 1) epinephrine levels have been elevated with systemic injections and 2) epinephrine levels have been reduced by removal of the main source of endogenous epinephrine, the adrenal medulla (McCarty & Kopin, 1979). Accordingly, the effects of these two manipulations are discussed below under separate headings. The Effects of Epinephrine Administration Five studies (see Table 1) have demonstrated an enhancement of aversive responding in rats injected with epinephrine. Rats 3 Table 1 Effects of Epinephrine Administration on Aversive Responding Paradigm Investigator Dosage Results Active Avoidance Two-way Sines (1959) Latane & Schachter (1962) Stewart & Brookshire (1967) Conner & Levine (1969) Gupta & Holland (1969) Moran, Ahmad, & Meagher (1970) (in sterile water, i.p.) .1 mg/kg .2 and .4 mg/kg (in oil, s.c.) .125 mg/kg 2.5 & 5.0 mg/kg (in oil,s.c.) .125 mg/kg 5.0 mg/kg (in oil, s.c.) .125 mg/kg (in distilled water, i.p.) 1.0 mg/kg 2.0,3.0, 4.0, and 5.0 mg/kg (in saline-glucose, i.p. .125 mg/kg (in oil, s.c. .125 mg/kg 0 no significant effect slower acquisition + faster acquisition 0 no significant effect no significant effect slower acquisition slower acquisition ? not assessed statistically decreased number of avoidance responses slower acquisition slower acquisition no significant effect on acquired task performance but increased trembling and shifts in activity (continued) 4 Table 1 — Continued Paradigm Investigator Dosage Results One-way Conditioned Suppression Escape Remington & Anisman (1974) Kosman & Gerard (1955) Moyer & Bunnell (1959) D'Amato & Schiff (1964) Leshner & Stewart (1966) Stewart & Brookshire (1968) Stewart & Brookshire (1968) (in saline, i .p.) .25 mg/kg (in oil, s.c .) 6.0 mg/kg (in saline, i .p.) . 3, .6 and .9 mg/kg (i .p.) .125 and .25 mg/kg (in oil, s.c.) .1 and 1.0 mg/kg 3.0 mg/kg (in oil, s.c.) .1, 1.0, 3.0, 5.0 and 7.0 mg/kg (in oil, s.c.) .1, 1.0, 3.0, 5.0 and 7.0 mg/kg decreased number of avoidance responses decrement in acquired task pe rformance no significant effect on acquisition 0 no significant effect on acquisition 0 no significant effect on ext inct ion greater mean running times no significant suppression of a licking response no significant effect on escape responding (continued) 5 Table 1 — Continued Paradigm Investigator Dosage Results Exposure to: Light and Noise Singer (1963) (in oil, s.c .) .05 and .1 mg/kg + increased defecation, urination, and trembling Leventhal & Killackey (1968) (in saline, i .p.) .08 mg/kg + increased time spent in the familiar compartment of a box Shocked in One Part of a Two-Compartment Box and Later Replaced in Box Ramano (1968) (in saline, i . p.) .1 mg/kg + decreased time spent in shock compartment Note. + increased, - = decreased, 0 = no significant, and = questionable effect on aversive responding. 6 receiving exogenous epinephrine and exposed to aversive stimuli consisting of a loud noise (e.g., the sound made by a buzzer) and a flashing light were found to exhibit increased trembling, urination, and defecation in one study (Singer, 1963) and increased defecation and an increase in the amount of time spent in the familiar compartment of a two-chamber box in another (Leventhal & Killackey, 1968). In a similar type of investigation (Kamano, 1968), rats injected with epinephrine were found to spend less time in the compartment of a box in which they had previously received footshock. Systemic epinephrine administration has also been found to facilitate acquisition of shuttle-box avoidance (Latane & Schachter, 1962); however, in an attempted replication (Moran, Ahmad, & Meagher, 1970) of this study, acquisition of avoidance responding was not enhanced by epinephrine administration, but trembling and shifts in type of activity were. In contrast, in the remaining 12 published studies of the effect of epinephrine administration on responses to aversive stimulation, epinephrine either produced no significant effect or actually reduced aversive responding. Epinephrine administration has either failed to affect or has impaired two-way active avoidance responding (Conner & Levine, 1969; Gupta & Holland, 1969; Moran et al., 1970; Remington & Anisman, 1974; Sines, 1959; Stewart & Brookshire, 1968), one-way active avoidance responding (D'Amato & Schiff, 1964; Kosman & Gerard, 1955; Leshner & Stewart, 1966; Moyer & Bunnell, 1959), conditioned suppression of responding (Stewart & Brookshire, 1968), and escape responding (Stewart & Brookshire, 1968). 7 The Effects of Epinephrine Depletion Four studies (see Table 2) have demonstrated the predicted disruption of responding to aversive stimuli in rats with their main source of endogenous epinephrine, the adrenal medulla, surgically removed. In these studies, adrenal enucleation caused a disruption of passive avoidance (Silva, 1973), conditioned suppression (Pare _ Cullen, 1971), and two-way active avoidance (Conner & Levine, 1969; Levine & Soliday, 1962). In one study (Conner & Levine, 1969), this effect was found to be reversible by the administration of exogenous epinephrine. In contrast, there have been almost twice as many published experiments (i.e., seven) in which adrenal enucleation has been found to have no significant effect on aversive responding. Adrenal-enucleation was found to have no significant effect on aversive responding in passive avoidance (Di Guisto, 1971; Silva, 1973), in conditioned suppression (Leshner, Brookshire, & Stewart, 1971), in two-way active avoidance (Moyer _ Korn, 1965), and in one-way active avoidance (Clancy & Caldwell, 1978; Moyer _ Bunnell, 1959; Silva, 1974) paradigms. EVALUATION OF THE STUDIES EXAMINING THE RELATIONSHIP BETWEEN EPINEPHRINE AND AVERSIVE RESPONDING The above studies have obviously been unsuccessful in elucidating the relationship between epinephrine levels and the behaviour of rats in aversive situations; the experimental results are so inconsistent that it is difficult to determine whether a reliable relationship between epinephrine and aversive responding even exists (Leshner, 1978; Smith, 1973). Although a variety of factors may have contributed to the 8 Table 2 Effects of Adrenal Demedullation on Aversive Responding Paradigm Investigator Results Active Avoidance Two-way One-way Passive Avoidance Levine & Soliday (1962) Moyer & Korn (1965) Conner & Levine (1969) Moyer & Bunnell (1959) Silva (1974) Clancy & Caldwell (1978) Di Guisto (1971) Silva (1973) + slower acquisition ° no significant effect on acquisition + slower acquisition {restored by administration of of epinephrine (.125 mg/kg in oil, s.c.)} no significant effect on acquisition no significant effect on acquisition no significant effect on extinction no significant effect on acquisition no significant effect on performance no significant effect on extinction when either 1.0-or .3-sec 1.0 mA shock was used faster extinction when .2 sec shock was used (continued) 9 Table 2 — Continued Paradigm Investigator Results Conditioned Suppression Pare & Cullen (1971) Leshner, Brookshire, & Stewart (1971) + less suppression of bar pressing for food ° no significant effect on suppression of a licking response Note. + = decreased and ° responding. = no significant effect on aversive 10 inconsistencies in the experimental results, the fact that some studies have involved learned responses and others innate responses to aversive stimulation may account for a substantial portion of the confusion. The term "innate" as used here refers to responses (e.g., fleeing, freezing, trembling, urination, defecation) that are exhibited in their complete form in the absence of relevant training. It is important to note that in only one (Latane' & Schachter, 1962) of the 12 studies involving a learned response (i.e., conditioned active avoidance) as the dependent variable was there an enhancement of aversive responding in response to the injected epinephrine. In contrast, four (Kamano, 1968; Leventhal & Killackey, 1968; Moran et al., 1970; Singer, 1963) of the six published attempts to facilitate innate aversive responses have met with success. As a result, some authors (e.g., Di Guisto, Cairncross, & King, 1970) have suggested that exogenous epinephrine may affect only innate responses to aversive stimulation. Although the validity of this proposition has yet to be established, it is undeniable that innate responses have proven to be more useful than learned responses in the study of the effects of epinephrine on responding in aversive situations. Reports of a relationship between epinephrine and innate responses, unfortunately, have had little impact in this area of behavioural endocrinology. Part of the reason for this lack of influence may be the predilection of psychologists for conditioned responses (Di Guisto et al., 1970). For example, Gupta and Holland (1969) refer to the freezing and crouching postures that delay acquistion of a conditioned avoidance 11 response as "abnormal reactions". There do, however, seem to be two specific problems with the particular innate responses to aversive stimuli that have been used to examine the behavioural effects of epinephrine. First, some of these responses, such as defecation and urination, are under the direct control of the sympathetic nervous system, and hence it is difficult to determine if an increased frequency of these behaviours is anything more than a direct peripheral nervous system effect of epinephrine. The most important question raised by behavioural studies of epinephrine is how epinephrine can influence complex behaviours under central nervous system control without penetrating the blood brain barrier. Second, other aversive responses (e.g., activity level and freezing) are ambiguous. Freezing, for example, is an ambiguous response in that it is difficult to determine if the rat is motionless (frozen) as a result of exposure to an aversive stimulus or is simply tired or otherwise debilitated. It appears then that if innate responses are to be used in the study of the relationship between epinephrine and aversive responding, the response chosen for study should meet at least two criteria. First, the behaviour in question should be a response to aversive stimulation that is not under direct sympathetic control; it should reflect an action of epinephrine mediated by the central nervous system. Second, the response topography must be unambiguous; the response should be clearly distinguishable as a response to aversive stimuli and should not closely resemble behaviours that occur in other situations. 12 GENERAL PURPOSE The general purpose of the present research was to determine the relationship between epinephrine levels and defensive burying, an innate response to aversive stimulation c that appears to satisfy both of the aforementioned criteria. Defensive burying, refers to the fact that rats typically respond to well-defined aversive stimuli by pushing moveable material towards and over them. This behaviour was first described by Hudson (1950) and has recently been labelled, quantified, and investigated by Pinel and his co-workers (e.g., Pinel _ Treit, 1978; Terlecki, Pinel, & Treit, 1979; Wilkie, MacLennan, & Pinel, 1979). The following review of defensive burying reveals that it satisfies the two criteria discussed above, and in addition offers a number of other advantages for use in the study of the relationship between epinephrine and responses to aversive stimuli. Defensive Burying  General Description of Defensive Burying In the standard burying paradigm, rats are exposed to an easily discernable aversive stimulus located in a small Plexiglas test chamber containing commercial bedding material. Rats placed in this situation displace the bedding material towards the aversive object — an activity that usually results in the object being covered with bedding by the end of the standard 15-min test period. Although the rats can use a variety of movements to direct material towards an aversive object, when commercial bedding or a similar homogenous material such as sand constitutes the only available material, burying behaviour is 13 highly stereotyped (Pinel & Treit, 1979). The rat typically approaches the aversive object from a distant part of the chamber and sprays the bedding forward with rapid pushing movements of its forelimbs. Thus, burying behaviour in this test situation is usually measured by recording the amount of time the rat spends engaged in this directed forelimb spraying and also by measuring the height of the bedding material accumulated at the test object at the end of the test session. Burying behaviour occurs in response to both unconditioned and conditioned aversive stimuli. It has been found that rats enter the experimental environment with a pre-existing tendency to bury some stimuli (unconditioned defensive burying) but not others. For example, rats buried an unset mousetrap or an unspent flashbulb when they were first encountered in a familiar test chamber, but not a length of polyethylene tubing or a wire-wrapped wooden dowel (e.g., Pinel, Hoyer, & Terlecki, 1980; Terlecki, Pinel, & Treit, 1979). Rats have also been found to bury selectively previously neutral stimuli that have been paired with any one of a variety of aversive stimuli (conditioned defensive burying). For example, in the most frequently used version of this paradigm rats bury a wire-wrapped wooden dowel once it has been the source of an electric shock (e.g., Pinel & Treit, 1978). However, rats have also been shown to bury neutral objects paired with such varied unconditioned aversive stimuli as airblast, flashing light, physical impact, toxicosis, or noxious taste (e.g., Terlecki et al., 1979; Wilkie, MacLennan, & Pinel, 1979). Although most studies of defensive burying have involved 14 adult, male, hooded, Long-Evans rats, burying is not specific to these subjects. Burying behaviour has been observed in both male and female rats and in rats as young as 30 days of age (Treit, Terlecki, & Pinel, 1980). Moreover, defensive burying is exhibited by other strains (e.g., Fisher, Long-Evans, Sprague-Dawley, Wistar) of rats (McKim _ Lett, 1979; Treit et al., 1980) and also by other rodents such as ground squirrels (Owings & Coss, 1977) and mice (Treit et al., 1980). Laboratory investigations and naturalistic observations have suggested that defensive burying has an adaptive function. This directed forelimb spraying response can have at least three different beneficial physical consequences for the rat. First, this response can result in potentially hazardous objects being completely covered with material (Coss & Owings, 1978; Terlecki et al., 1979). Second, it can serve to drive off predators (e.g., snakes) and aggressive conspecifics (cf. Coss _ Owings, 1978; Owings _ Coss, 1977). And third, it can result in the formation of barriers that can impede the approach of aggressive conspecifics (Calhoun, 1962) or members of other species (Coss & Owings, 1978; Terlecki, Pinel, & Spetch, 1980). Defensive Burying and Epinephrine Defensive burying clearly meets both of the previously described criteria for a behavioural response intended for use in studying the relationship between epinephrine and behaviour in aversive situations. First, burying behaviour is a complex behaviour that obviously is not under the exclusive control of the sympathetic nervous system. Second, burying is a highly stereotyped response to aversive stimuli that is easily 15 recognized and scored. High degrees of agreement have been found between independent observers scoring the duration of this behaviour: Davis, Whiteside, Heck, Dickson, & Tramill (in press); Pinel, Hoyer, & Terlecki (1980); Pinel, Treit, and Wilkie (1980); and Davis and Rossheim (in press) have reported correlations of .95, .98, .988, and .93, respectively. The defensive burying paradigm also has a number of other features that may prove useful in the study of the effects of epinephrine on aversive responding. First, because burying behaviour occurs in response to both conditioned (e.g., Pinel & Treit, 1978; Terlecki et al., 1979) and unconditioned (e.g., McKim & Lett, 1.979; Terlecki et al., 1979) aversive stimuli, it is possible to assess the effect of epinephrine on aversive responding to both of these types of aversive stimulation. Some investigators (e.g., Stewart & Brookshire, 1968) have argued that exogenous epinephrine may enhance innate responses to unconditioned aversive stimuli but not those to conditioned aversive stimuli. The validity of this proposition can be assessed by examining the effects of altering epinephrine levels on both kinds of defensive burying. Second, by using the defensive burying paradigm to study the effects of epinephrine on aversive responding, it is possible to avoid one of the confounds inherent in most of the previously described studies. In many of the epinephrine-administration studies and in all of the epinephrine-depletion studies, epinephrine levels have been altered during both the conditioning and testing phases of the experiment, thereby confounding the effects of epinephrine on aversive responding 16 with its possible effects on conditioning and memory; besides affecting the animals' response to aversive stimulation, alteration of epinephrine levels may be affecting such processes as the formation of associations (cf. Stewart & Brookshire, 1968) and their storage in memory (Gold & van Buskirk, 1975). Interpretation of the results of such studies is therefore difficult. The unconditioned defensive burying paradigm involves no conditioning phase, and thus could be used to circumvent this difficulty. The conditioned defensive burying paradigm may also prove to be useful in this respect because significant amounts of burying are displayed by rats tested many days after a single conditioning trial (Pinel & Treit, 1978). Because conditioning and testing phases can be easily separated in time using this paradigm, epinephrine levels could be selectively altered during the testing phase of the experiment. Third, it is easy to produce a control level of burying against which an enhancement or disruption is readily detectable. The amount of burying displayed by rats during a given test session can be controlled by varying the amount of prior exposure to the aversive stimulus (Terlecki et al., 1979), the length of the interval between conditioning and testing (Pinel & Treit, 1978), the intensity of the aversive stimulus (Treit et al., 1980), or the size of the chamber (Pinel, Treit, Ladak, & MacLennan, 1980). Fourth, because the burying response is an active motor behaviour, any enhancement of this response is readily distinguishable from an impairment of motor functioning. Because a number of studies (e.g., Kosman & Gerard, 1955; Leshner & 17 Stewart, 1966; Manto, 1967) have established that high levels of epinephrine are physically debilitating, some experimenters (e.g., Di Guisto et al., 1971) have warned that administration of epinephrine may be an unsuitable technique for assessing the effects of epinephrine on aversive responding. This criticism may be valid when applied to paradigms that involve an inhibition of active responding (e.g., conditioned suppression and passive avoidance paradigms) because it might be difficult j to differentiate between an enhancement of responding and an impairment of locomotor function using these paradigms. The burying paradigm, however, is free from this problem. PURPOSE The general purpose of the present investigations was to determine the relation between systemic epinephrine and the defensive burying response. The experimental approach that was used to establish this relation involved the manipulation of circulating epinephrine levels. Peripheral levels of epinephrine were either increased by injection of exogenous epinephrine or depleted by removing the primary source of endogenous epinephrine, the adrenal medulla. The individual experiments were, thus, of two types. The first set of studies involved the effects of systemic epinephrine injections on defensive burying (Experiments 1 to 4). The second involved an examination of the effect of adrenal demedullation on defensive burying (Experiments 5 and 6) and also of the ability of replacement injections of epinephrine to reverse this effect (Experiment 6). Although the results of previous studies had suggested that epinephrine could affect responses in aversive situations, no 18 previous studies had been able to demonstrate a reliable and systematic relation between peripheral epinephrine and such behaviour. GENERAL METHODS There are a number of methodological features that are common to the six experiments included in this dissertation. These general features are described below. Subjects The subjects used in each of the experiments were naive, male, Long-Evans hooded rats purchased from Canadian Breeding Farm and Laboratories, La Prairie, Quebec. The rats were housed in groups of either four or six in 41 X 25 X 18 cm and 63 X 25 X 18 cm wire-mesh cages, respectively. Purina laboratory chow and water were available continuously in the home cages. The rats were housed under a 12-hr light/12-hr dark cycle. Apparatus The rats were tested individually in a small, isolated room adjacent to the behavioural recording apparatus. The test chamber was a 44 X 30 X 44 cm transparent Plexiglas box, the floor of which was covered with a 5 cm layer of regular grade San-i-cel, a commercial bedding material made of ground corncob (Paxton Processing Co., Paxton, Illinois). The rat's behaviour was monitored via a television camera mounted 50 cm directly above the test chamber. The duration of burying, that is, the amount of time the rat spent engaging in directed forelimb spraying, was recorded on an event recorder. The occasional movement of material with responses other than forelimb spraying and/or in directions not towards the aversive object was noted 19 separately. This type of behaviour, observed only once in these studies, did not contribute to the duration-of-burying score. General Procedures Habituation Prior to each experiment, all rats were given a subcutaneous (s.c.) injection of isotonic saline (1 ml/kg) and placed in the test chamber with their cagemates in groups of four or six for 30-min periods, each day for 4 consecutive days. Behavioural Observation and Quantification Although the conditioning phase differed from experiment to experiment, all testing phases were conducted similarly. On the testing day, during the light phase of the rats' light/dark housing cycle each rat was placed individually into the test chamber and a 15 min test session was initiated. During this test session, the duration of burying was recorded, and following each test, the absolute height of the bedding material at the aversive stimulus was measured and recorded. EFFECT OF EXOGENOUS EPINEPHRINE ON DEFENSIVE BURYING Experiment 1 The purpose of the first experiment was to demonstrate that an increase in systemic epinephrine levels enhances the defensive burying of a conditioned aversive stimulus. Conditioned rather than unconditioned defensive burying was selected for study for two reasons. First, conditioned defensive burying had proven to be slightly more robust; it had been more common for burying behaviour to be displayed by every rat in a group exposed to a conditioned aversive stimulus than an unconditioned stimulus (cf. Pinel, Hoyer, & Terlecki, 1980; 20 Terlecki et al., 1979). Second, conditioned defensive burying had been more thoroughly investigated than had unconditioned burying, thus there was a more solid foundation of parametric data for this form of the burying paradigm. Previous investigations had shown that the conditioned defensive burying response is extremely reliable and is readily controlled by various experimental parameters that are easily manipulated by the experimenter. For example, a direct and reliable relation had been demonstrated between conditioned defensive burying and the intensity of the UCS; Treit, Pinel, and Terlecki (1980) had found that rats spent more time burying a wooden dowel if it had been the source of high intensity shock. Conditioned defensive burying had also been found to decrease as the delay between conditioning and testing increased (Pinel & Treit, 1978) and as a function of repeated tests with the aversive object following a single conditioning trial (Terlecki, unpublished data). By manipulating these experimental parameters (i.e., intensity, delay, and exposure), a level of defensive burying can be produced that is suitable for demonstrating a facilitatory effect of epinephrine. Pilot studies confirmed the efficacy of this approach, and the experimental parameters used in Experiment 1 were chosen on the basis of the resulting data. Method On Day 5, following the 4 habituation days, a 6.5 X .5 X .5 cm wooden, wire-wrapped dowel was mounted in the centre of one end wall of the test chamber. The dowel was attached so that it was parallel to the- floor and side walls of the chamber, at a height 2 cm above the bedding material. During this conditioning 21 day, each of the 20 306- to 402-gm rats used in Experiment 1 was placed individually in the centre of the chamber, facing away from the dowel. Each rat then received a single conditioning trial; the first forepaw contact with the dowel resulted in the rat receiving a brief electric shock. The shock, initiated by the experimenter and terminated by the withdrawal of the rat, was delivered between the two uninsulated wires that were wrapped around the dowel and connected to a constant-current shocker. The actual duration and intensity of the shock received by each rat was monitored with a storage oscilloscope. Analysis of these data showed that the rats received shocks averaging 1.9 mA (SD = .2 mA) in intensity and 36 msec (SD =12.6 msec) in duration. After a rat was shocked, it was immediately removed from the chamber. Each rat was then randomly assigned to either an epinephrine experimental group (n= 10) or a saline control group (n=10). On the following day, prior to being placed in the test chamber, the rats in the experimental group were injected (s.c.) with a .1 mg/kg dose of epinephrine HC1, diluted in isotonic saline to a concentration of .2 mg/ml, and the rats in the control group were injected (s.c.) with an equivalent volume (.5 ml/kg) of isotonic saline. The injections were administered 1 min prior to testing because epinephrine in a saline vehicle starts to produce its peripheral nervous system effects within 5 min of its subcutaneous administration (Gold & van Buskirk, 1975; Goodman & Gilman, 1975). Although no further shocks were administered, the rats were given an injection and were tested each day for 4 consecutive days. Testing was carried out over 4 days in order to increase the probability of finding an 22 enhancement of defensive burying; as previously mentioned, the amount of burying exhibited by rats decreases as the amount of exposure to the conditioned stimulus increases. Results and Discussion It is apparent from Figure 1 that systemic injections of epinephrine enhanced the conditioned defensive burying of the shock source. The epinephrine-injected rats spent significantly [F(l,18) = 4.39, p_ < .05] more time spraying bedding material at the dowel (see panel A) than did their saline-injected controls. These behavioural observations were confirmed by analysis of the height of the material accumulated by the rats at the dowel (see panel B). The rats that were injected with epinephrine accumulated significantly [F(l,18) = 4.45, p < .05] higher piles of bedding at the dowel than did the rats that were injected with saline. These results established that injected epinephrine can enhance aversive responding and demonstrated that the conditioned defensive burying paradigm is sensitive to this effect. It is also evident from Figure 1 that the amount of burying exhibited by both groups of rats declined over testing sessions. This finding confirms my unpublished observation that the total amount of burying exhibited by rats during a given test session decreases with repeated exposure to the conditioned aversive stimulus. Statistical analyses confirmed that the duration of burying [Figure IA; F(3,54) = 27.73, r; < «05] and height of material at the dowel [Figure IB; F(3,54) = 27.01, p < «05] decreased significantly over testing days. Although the decline in the duration of burying observed over days was not 23 Figure 1. Mean duration of burying (panel A) and mean final height of bedding material at the dowel (panel B) on 4 testing days for rats injected with epinephrine and rats injected with saline. The dotted line in panel B indicates the original height of the bedding material. MEAN DURATION OF BU.RYING (sec) MEAN HEIGHT OF MATERIAL AT THE DOWEL (cm) 25 significantly different in the two groups [F(3,54) = .15, p > .05], the epinephrine-injected rats displayed less of a reduction in height scores over days than did the saline-injected rats [F(3,54) = 5.85, p_ < .05]. This may have been due to the fact that even though the amount of time that the epinephrine-injected rats spent burying was decreasing, they appeared to be performing a greater percentage of their forelimb spraying from positions close to the dowel, and thus could have been progressively more efficient in accumulating material directly over it. Experiment 2 Almost all the studies of the effect of exogenous epinephrine on responding in aversive situations have employed shock as the aversive stimulus thereby limiting the generality (Leshner, 1978) and perhaps the ethological significance of the results. Thus, the purpose of the second experiment was to extend the results of Experiment 1 by using a flash of light instead of electric shock as the unconditioned aversive stimulus. Terlecki, Pinel, and Treit (1979) were the first to report that rats would bury a previously "neutral" object that had been the source of a flash of light. They found that rats buried an unspent flashbulb in a protective collar when they first encountered it in the test chamber, and that this unconditioned burying disappeared following 4 habituation days. When habituated subjects were subsequently exposed to a flash from the bulb, however, 7 out of 10 rats buried the flash assembly. The best evidence that the burying of flash sources reflects a 26 form of associative learning was provided by an experiment in which two comparable flash assemblies were present in the test chamber during habituation, conditioning, and testing. In this situation rats pushed bedding towards, the source of the light flash, but not towards the control assembly. Method The experimental procedure was the same as that employed in Experiment 1 with the following exceptions. First, the unconditioned aversive stimulus was a flash of light produced by an AG1B flashbulb. This flashbulb was encased in a grey plastic collar (3 cm in diameter and 5 cm in length) in order to protect the 20 338- to 472-gm subjects from the heat generated by the flashbulb. The closed end of this assembly was attached to the test chamber so that it was 1 cm above the level of the bedding material. During the conditioning session, the flash was triggered by the experimenter when the rats were facing the flashbulb and touching the collar with a forepaw. Second, the flash assembly was present in the test chamber for the 4 habituation days in order to reduce any neophobic responses to the assembly that could potentially interfere with the conditioning session. Results and Discussion Figure 2 shows the mean duration of burying (panel A) and the height of the piles of material accumulated at the flashbulb assembly (panel B) by both groups of rats during the 4 test days. Rats injected with epinephrine spent substantially more time spraying bedding towards the flashbulb, and thus accumulated higher piles of bedding at the flashbulb, than did 27 Figure 2. Mean duration of burying (panel A) and mean final height of bedding material at the flashbulb (panel B) on 4 testing days for rats injected with epinephrine and rats injected with saline. The dotted line in panel B indicates the original height of the bedding material. DAY OF TESTING 29 rats injected with saline. The significance of these differences was established by analyses of variance for repeated measures [duration effect: F(l,54) = 10.5, p < .05; height effect: F(l,54) = 12.01, £ < .05]. The observation that systemic injections of epinephrine enhance defensive burying of a flashbulb assembly paired with a flash of light provides evidence that the facilitative effect of epinephrine on conditioned burying is not specific to situations in which electric shock is the unconditioned stimulus. Analysis of the effect of repeated testing showed that both groups of rats spent less time burying the flashbulb in the later test sessions [F(3,54) = 3.33, p_ < .05]. This decrease, however, was not as pronounced for the saline-injected rats because their duration of burying scores were so low to begin with [interaction effect: F(3,53)= 2.88, p < .05]. This decrease in burying over days was also reflected in the height of bedding scores [F(3,54) = 2.86, p <.05]. No significant interaction effect [F(3,54) = 2.15, p > .05] occurred for this score, however. After the second day of testing, two of the rats in the saline group actually spent a portion of the test period digging in the San-i-cel underneath the flashbulb assembly thereby producing mean height scores below the 5 cm baseline. Although 6 of the 10 rats injected with saline displayed some burying on the first day of testing, the mean duration of burying was only .9 sec. Pinel and Treit (1978) had found that the conditioned defensive burying of a shock source declines with increases in the duration of the conditioning-test interval. The low levels of burying in the present study suggest 30 that the burying conditioned by a flash of a bulb also declines with increases in the time between conditioning and testing; rats tested immediately after the flash spent about 31.8 sec burying the bulb in the Terlecki et al. study. Experiment 3 Because facilitative effects of epinephrine on responses to conditioned aversive stimuli had been difficult to demonstrate, it had been suggested that epinephrine might have a differential effect on responding to conditioned and unconditioned aversive stimuli (e.g., Stewart & Brookshire, 1968). The purpose of the third experiment was to demonstrate that epinephrine would facilitate unconditioned defensive burying as it had conditioned defensive burying. Method The experimental procedure employed in Experiment 3 was similar to that used in Experiments 1 and 2 except for the following changes. First, because no conditioning session was necessary, testing of the 20 367- to 575-gm rats serving as subjects started on the day following the fourth habituation session (Day 5). Second, on the testing day, an unset 9.8 X 4.5 X .5 cm wooden mousetrap (Victor; Woodstream Corporation, Lilitz, Pennsylvania), an object previously demonstrated to be an effective unconditioned aversive stimulus for defensive burying (Terlecki et al., 1979), was attached to the test chamber wall. The side of the trap was fastened horizontally to the centre of the end wall so that it was 1 cm above the level of the bedding material. 31 Results and Discussion Figure 3 shows that injected epinephrine enhanced unconditioned defensive burying. Rats that had been injected with epinephrine spent significantly [F(l,54) = 8.97, £ < .05] more time burying the trap (see panel A) and as a result accumulated significantly [F(l,54) = 8.92, £ < .05] higher piles of bedding at the trap (see panel B) than did rats that had been injected with saline. The results of this experiment extend the findings of Experiments 1 and 2; increased peripheral levels of epinephrine enhance defensive burying of unconditioned as well as conditioned aversive stimuli. Analysis of the effect of repeated testing revealed that both groups of rats engaged in decreasing amounts of burying over days [duration effect: F(3,54) = 10.45, £ < .05; height effect: F(3,54) = 8.31, £ < .05]. Rats in both injection conditions displayed a similar pattern of reduction of unconditioned defensive burying over days [interaction effect for duration: F(3,54) = 1.05, £ > .05; interaction effect for height: F(3,54) = 1.14, £ > .05]. Experiment 4 Although the results of the first three experiments had clearly demonstrated that systemic injections of epinephrine can enhance the defensive burying of both conditioned and unconditioned aversive stimuli, the same dose (.1 mg/kg) of epinephrine had been administered in all three studies. The purpose of the fourth experiment was to establish that the effect of systemic epinephrine on conditioned defensive burying is not restricted to this one particular dose and that the 32 Figure 3. Mean duration of burying (panel A) and mean final height of bedding material at the trap (panel B) on 4 testing days for rats injected with epinephrine and rats injected with saline. The dotted line in panel B indicates the original height of the bedding material. MEAN DURATION OF BURYING (sec) 34 magnitude of the effect is a function of dose. Method The procedure used in this experiment was the same as that employed in Experiment 1 except for the following changes. Analysis of the actual duration and intensity of shock received by each rat revealed that the 50 410- to 687-gm rats serving as subjects in this experiment received shocks averaging 1.84 mA (SD = .23 mA) in intensity and 47.5 msec (SD =40.07 msec) in duration (cf. Experiment 1). After being shocked, the rats were assigned to one of five injection conditions (n = 10). Each rat was then given a subcutaneous injection of one of four different doses (.01, .1, .5, or 2 mg/kg) of epinephrine diluted in saline so that each rat was given the same volume (3 ml/kg) of fluid, or an equivalent volume of the saline vehicle (0 dose). A single test session was conducted 1 min after each rat was injected. The duration of burying and the final height of material at the dowel were recorded by an observer that was unaware of the dose of epinephrine administered to each rat. Results and Discussion It is apparent from Figure 4 that the dose of epinephrine administered to the rats produced an effect on the amount of conditioned defensive burying. One-way analyses of variance confirmed that there was a significant effect of dose on both the duration of burying [F(4,45) = 9.86, p_ < .05] and the height of material accumulated at the dowel [F(4,45) = 8.82, p_ <.053 . Subsequent trend analyses (trend analysis for an independent variable with unequal spacing; Keppel, 1973) indicated a significant linear trend [duration effect: 35 Figure 4. Mean duration of burying (panel A) and mean final height of bedding material at the dowel (panel B) for rats injected with one of five different doses of epinephrine. The dotted line in panel B indicates the original height of the bedding material. DOSE OF EPINEPHRINE (mg/kg) 37 F(l,45) = 14.23, 2 < -05? height effect: F(l,45) =19.64, £ < .05] and also a significant quadratic trend [duration effect: F(l,45) = 19.95, £ < .05; height effect: F(l,45) = 13.53, 2 < .05] in both sets of scores. As can be seen in Figure 4, both the duration of burying (panel A) and the height of material at the dowel (panel B) increased with the increasing doses of epinephrine up to the 2 mg/kg dose, which produced a substantial decrement in conditioned defensive burying. The behaviour of the rats that received the 2 mg/kg of epinephrine was strikingly different from the behaviour of the rats receiving either saline or one of the other three doses of epinephrine. Only 3 of the 10 rats injected with 2 mg/kg of epinephrine moved any bedding in the direction of the dowel during the test session; whereas, all 10 of the rats in each of the other four injection conditions engaged in burying behaviour. The rats receiving the 2 mg/kg dose of epinephrine spent most of the test period lying relatively motionless at the back of the test chamber. The infrequent locomotor movements exhibited by these rats usually involved a "swimming" type motion in which the rat's limbs were splayed to the side and its ventral surface was touching the bedding material, thus indicating a gross impairment of motor function. The results of this experiment confirm those of Experiment 1 and demonstrate that the facilitative effect of epinephrine on conditioned defensive burying is not restricted to a single dose of epinephrine. In addition the amount of defensive burying was found to increase with the increasing doses of epinephrine used in this study until a level of epinephrine was reached that 38 produced gross motor impairment. EFFECT OF DEMEDULLATION ON DEFENSIVE BURYING Although the results of the first four experiments clearly demonstrated that systemic injections of epinephrine have a facilitative effect on both conditioned and unconditioned defensive burying, these findings do not allow one to make conclusive statements regarding the role of endogenous epinephrine in aversive situations. It is possible that the enhancement of defensive burying observed in the first series of experiments is simply an artificial effect resulting from increasing epinephrine levels well beyond those normally produced in aversive situations, and that the fluctuations in the levels of endogenous epinephrine normally produced in aversive situations would be without effect on behaviour. Another way of obtaining evidence that the epinephrine released from the adrenal glands in response to aversive stimulation has a modulating effect on aversive responding is to assess the effect of reductions in the level of epinephrine. Accordingly, the purpose of the second set of studies was to examine the effect on defensive burying of reducing epinephrine levels. Epinephrine levels were reduced by removing the rats' primary source of epinephrine, the adrenal medulla. If the function of endogenous epinephrine is consistent with the role suggested by the first set of studies included in this dissertation, then reductions in epinephrine levels should reduce defensive burying. 39 Adrenal Anatomy The adrenal glands of the rat are two small (approximately 4 X 3 X 2.8 mm), rounded, brown bodies situated in the retroperitoneal fat slightly anterior to the kidneys (Hebel & Stromberg, 1976; Rowett, 1974). The adrenal is enclosed by a thin capsule of connective tissue and consists of two distinct and functionally different types of endocrine tissue. The superficial layer of tissue, the adrenal cortex, arises embryologically from the coelemic mesoderm on the medial side of the urogenital ridge. The adrenal cortex which is divided into three morphologically distinguishable zones, the zona glomerulosa, the zona fasciculata, and the zona reticularis, produces a number of hormones including the mineral corticoids, the glucocorticoids, and the adrenal sex steroids. Completely surrounded by the adrenal cortex is the second type of tissue, the adrenal medulla. It arises embryologically from the ectodermal neural crest, tissue and is a functional part of the sympathetic nervous system. The adrenal medulla is innervated by the splanchnic nerve, which forms a cholinergic synapse with the chromaffin cells of the medulla. Stimulation of the splanchnic nerve causes the chromaffin cells to release the hormones epinephrine and norepinephrine directly into the adrenal vein (cf. Bloom & Fawcett, 1968; Kopin, 1980). Almost all (greater than 90 %) of the rats' circulating epinephrine comes from the chromaffin cells of the adrenal medulla (McCarty & Kopin, 1979). Adrenal Demedullation When the adrenal gland is demedullated, the adrenal capsule is cut and the adrenal medulla plus most of the surrounding 40 cortex is gently squeezed out, leaving behind only the capsule and a thin subcapsular portion of cortical tissue (e.g., Evans, 1936; Ingle & Griffith, 1949). In the weeks following this operation, the adrenal cortex regenerates. Cortical regeneration is typically complete within 3 to 6 weeks (e.g., de Groot & Fortier, 1959; Evans, 1936; Ingle & Griffith, 1949), and at this time plasma free corticosteroids are found to be at normal levels (Conner & Levine, 1969; Fortier & de Groot, 1959). Plasma epinephrine, on the other hand, is found to remain at less than 10% of basal levels following demedullation (McCarty & Kopin, 1979; Micalizzi & Pals, 1979). Experiment 5 The purpose of the fifth experiment was to assess the effect of reducing epinephrine levels on defensive burying. As was previously mentioned, one problem with all previous studies of the effect of epinephrine depletion on behaviour in aversive situations is that the effect of reducing epinephrine levels on aversive responding has been confounded with its possible effect on conditioning. This problem was avoided in the present experiment by using the unconditioned defensive burying paradigm. Method The 24 287- to 348-gm rats used in this experiment were randomly divided into two groups (n = 12). Rats in one group (demedullated) had their adrenal glands enucleated, and the rats in the other group ("sham-surgery") were treated comparably except that their adrenal glands were left intact. Surgery. All.rats were anesthetized with sodium pentobarbital 41 (Nembutal, 50 mg/kg, i.p.) and were shaved just caudal to the rib cage on both sides. The rats in the demedullated group were then given bilateral adrenal medullectomies following the procedure described by Ingle and Griffith (1949). Using a pair of scissors, a lateral incision was made in the skin and the muscle of the body wall, caudal to the rib cage and adjacent to the kidney. The kidney was manipulated through the opening in the body wall, and the adrenal gland was located and exposed. The adrenal gland was brought into the opening and held there with a pair of small curved forceps, the tips of which had been covered with polyethylene tubing. A piece of silastic tubing had been placed over the arms of the forceps in such a way that the polyethylene-covered tips could be brought together readily without being completely closed. This made it possible to hold the adrenal gland at its base without crushing the adrenal artery or vein. With the aid of a 16-power surgical microscope, an incision was made in the distal end of the adrenal gland with a small, sharp pair of scissors. Next the adrenal medulla and surrounding cortex were gently squeezed out of the adrenal capsule with a second pair of small curved polyethylene-tipped forceps. The kidney was then returned to the body cavity and the incised muscle and skin were sutured. This entire procedure was then repeated on the other side of the body. The rats in the sham-surgery group were subjected to the same surgical procedure except that the adrenal gland was not cut and enucleated. Following surgery both water and .9 % saline were made freely available to the rats in their home cages. The presentation of saline is a standard procedure after adrenal medullectomy 42 because it involves damage to the adrenal cortex, although this procedure may not be necessary (Gacent, Renzi, Gisoldi, & Howie, 1967). Behavioural testing. Behavioural testing commenced 2 months after surgery. Following the 4 habituation days, the unset mousetrap used in Experiment 3 was attached to one end wall of the test chamber. Each rat was then placed individually in the chamber and tested in the presence of the trap. Histology. At the conclusion of testing, the demedullated rats were sacrificed in a C02 chamber and perfused intracardially with .9 % saline and a 10 % solution of formalin. The adrenal glands were then removed, fixed in formalin, sectioned at 40 micron intervals with a freezing microtome, and stained with hematoxylin (modified Delafield's Hematoxlyin, Fisher Scientific Company) and eosin (Eosin Y, Fisher Scientific Company). Results and Discussion As can be seen in Figure 5, adrenal demedullation resulted in a substantial decrease in unconditioned defensive burying. Statistical analyses, t-tests for independent measures, confirmed that the demedullated rats spent significantly [t(22) = 2.10,rj < '05] less time burying and accumulated significantly [t(22) = 2.09, £ < .05] smaller piles of bedding at the trap than did rats in the sham-surgery group. Histological examination of the adrenal glands of the rats that had undergone adrenal enucleation revealed regeneration of the cortex but not the medulla, thus confirming the completeness of the demedullation. 43 Figure 5. Mean duration of burying (panel A) and mean final height of bedding material at the trap (panel B) for rats that had their adrenal glands demedullated and rats that had "sham" operations. The dotted line in panel B indicates the original height of the bedding material. 44 45 The results of this study demonstrate that depleting epinephrine levels by demedullating the adrenal glands can cause a significant reduction in aversive responding and that the unconditioned defensive burying paradigm is sensitive to this effect. This finding provides supporting evidence for the proposition that the epinephrine-induced enhancement of defensive burying found in the first set of studies reflects the effects of endogenous epinephrine in aversive situations. Experiment 6 The results of Experiment 5 demonstrated that adrenal demedullation can cause a reduction in unconditioned defensive burying. If as was suggested this effect is due to the depletion of endogenous epinephrine, then injections of epinephrine should attenuate or negate the reduction in unconditioned burying caused by adrenal demedullation. The purpose of Experiment 6 was to confirm the results of Experiment 5 and to demonstrate that the effects of adrenal demedullation on unconditioned defensive burying can be reversed by replacement injections of epinephrine. Method The surgical and behavioural testing procedures used in this experiment were the same as those employed in Experiment 5 except for the following changes. In the present experiment, there were 36 325- to 468-gm rats in both the demedullated and the sham-surgery groups. Prior to behavioural testing, the rats in each of these two groups were randomly assigned to one of three different drug conditions (n = 12). The rats were injected (s.c.) with either a .5 or 1 mg/kg dose of epinephrine diluted 46 in saline to concentrations of .25 mg/ml and .5 mg/ml respectively or an equivalent volume (2 ml/kg) of the saline vehicle (0 dose). Thus, the design was a 2 by 3 factorial with two types of operation and three different doses of epinephrine. The rats were injected 1 min prior to testing. The duration of burying and height of material at the trap were recorded by an observer that was unaware of each subject's experimental history. Results and Discussion Figure 6 shows the amount of burying exhibited by the rats in each of the six groups. The demedullated rats in general engaged in less burying behaviour than did the rats in the sham-surgery group. It is also evident from Figure 6 that epinephrine dosage had an effect on unconditioned defensive burying. The amount of burying exhibited by rats in both the demedullated and sham-surgery groups increased with increasing doses of epinephrine. The significance of these differences was established with two-way analyses of variance for independent measures. The rats in the demedullated group spent significantly [F(l,66) = 5.57, p < .05] less time spraying bedding material at the trap, and as a consequence they accumulated significantly [F(l,66) = 4.13, p < .05] less material at the trap than did the rats in the sham-surgery group. There was also a significant overall effect of the dose of epinephrine on the the amount of time spent burying [duration effect: F(12,66) = 4.77, p < .05; interaction effect: F(2,66) = .86, p > .05] and the amount of material accumulated at the trap [height effect: F(2,66) = 4.06, p < .05; interaction effect: F(2,66) = .87, p > .05]. 47 Figure 6. Mean duration of burying (panel A) and mean final height of bedding material at the trap for demedullated and "sham" control rats injected with one of three different doses of epinephrine. The dotted line in panel B indicates the orginal height of the bedding material. MEAN DURATION OF BURYING (sec) MEAN HEIGHT OF MATERIAL AT THE TRAP (cm) cn CO N CO CD 87 49 Subsequent trend analyses performed on the dosage effect indicated a significant linear trend [duration effect: F(l,66) = 9.5, £ < .05; height effect: F(l,66) = 7.5, 2 < -°5^ in both sets of data; both the duration of burying and the height of material at the trap increased as the dosage of epinephrine increased. The findings of this study confirm those of Experiment 5 and provide additional support for the proposition that endogenous epinephrine modulates aversive responding. As in Experiment 5, adrenal demedullation resulted in a substantial reduction of unconditioned defensive burying. This effect was reversed, however, by the administration of exogenous epinephrine; systemic injections of epinephrine enhanced the defensive burying exhibited by demedullated rats. In addition, the results of this experiment extend the results of Experiment 4. In Experiment 4 the facilitative effect of epinephrine on conditioned defensive burying was found to be dose-dependent; conditioned burying increased with the increasing doses of epinephrine used in this study until a level of epinephrine was reached that produced a gross motor impairment. The results of the present experiment establish that this dose dependency is not restricted to conditioned defensive burying; the amount of unconditioned burying exhibited by intact rats increased with the increasing doses of epinephrine used in this study. GENERAL DISCUSSION The general discussion is organized around two main topics. First, the two major accomplishments of the present studies are 50 separately discussed. Second, possible reasons for the concentration of previous experimenters interested in the relationship between epinephrine levels and behaviour on conditioned active avoidance paradigms are discussed along with a possible reason for the inconsistency of the results obtained from such studies. Accomplishments of the Present Studies The introduction of the burying paradigm as a vehicle for studying the relationship between epinephrine and responding to aversive stimulation resulted in two major accomplishments. First, the present six experiments provided two complementary types of evidence supporting the hypothesis that epinephrine has a modulating effect on behaviour in aversive situations. Second, this thesis provided an important extension of previously existing evidence suggesting that the relationship between epinephrine levels and responding to aversive stimulation can be characterized by an inverted U-shaped curve. These two contributions are discussed below under separate headings. Evidence for a Behavioural Effect of Epinephrine Two types of evidence were provided by the present six experiments that support the hypothesis that systemic epinephrine can have a modulating effect on behaviour exhibited in response to aversive stimulation. First, injections of epinephrine were found to facilitate defensive burying. This enhancement of defensive burying was found to be both reliable and general; it was not specific to either a particular type of aversive stimulus or to a particular dose of epinephrine. Epinephrine injections enhanced the defensive burying of both 51 unconditioned (of an unset mousetrap, Experiment 3) and conditioned (of a wire-wrapped wooden dowel paired with shock, Experiment 1; of a flashbulb assembly paired with a flash of light, Experiment 2) aversive stimuli. Also, five different doses of epinephrine ranging from .01 to 2 mg/kg were used in the studies included in this dissertation. All of these doses except for the 2 mg/kg dose, which produced an obvious impairment of locomotion, were found to have a facilitative effect on defensive burying. Furthermore, the injections of epinephrine appeared to affect defensive burying in a dose-related fashion. Burying of both conditioned (Experiment 4) and unconditioned (Experiment 6) aversive stimuli was found to increase with the increasing doses of epinephrine (except for the 2 mg/kg dose) used in the present studies. The second type of evidence for the hypothesis that epinephrine has a modulating effect on responses to aversive stimulation was provided by two experiments in which the adrenal gland was demedullated. In Experiments 5 and 6, removal of the rats' main source of endogenous epinephrine, the adrenal medulla, reduced unconditioned defensive burying. Moreover, a replacement injection of epinephrine administered to demedullated subjects counteracted the effects of demedullation on burying; systemic injections of epinephrine were found to increase the amount of burying exhibited by demedullated rats. Evidence Concerning The Nature Of The Relationship Between  Epinephrine and Aversive Responding It has been repeatedly suggested that the relationship between epinephrine level and behaviour in aversive situations 52 can best be characterized by an inverted U-shaped curve (e.g., Conner & Levine, 1969; Latane' & Schachter, 1962; Smith, 1973). Investigators have suggested: 1) that there is reduced responding to aversive stimulation in the absence of epinephrine, 2) that levels of responding increase as levels of epinephrine approach normal levels, 3) that they continue to increase as levels of epinephrine are increased above normal levels, and finally 4) that at high levels of epinephrine performance is disrupted. Four types of evidence have been provided to support these suggestions. Smith (1973), for example, listed the following findings as evidence for such an inverted U-shaped relationship between epinephrine level and aversive responding: 1) Conner and Levine's (1969) finding that adrenal demedullation retarded acquisition of a two-way active avoidance response, 2) Conner and Levine's (1969) finding that systemic injection of a small dose of epinephrine increased the rate of acquisition of avoidance responding in demedullated rats, 3) Latane and Schachter's finding that systemic injection of a small dose of epinephrine facilitated acquistion of a two-way active avoidance response in intact rats, and 4) Kosman and Gerard's (1950) finding that systemic injection of a large dose of epinephrine disrupted performance of one-way active avoidance response in intact rats. Such evidence is questionable for two reasons. First, evidence of a particular function that requires comparison between different types of experiments performed by different experimenters using different paradigms is tenuous at best. Second, the studies cited to support the idea of such an 53 inverted U-shaped relation are not representative of the existing literature. When experimental results are so inconsistent, support garnered from a few carefully selected studies is unconvincing to say the least. The present findings all provide evidence of such an inverted U-shaped relationship. For example, Experiment 6 constitutes the only instance in which responses to an aversive stimulus were reduced by epinephrine depletion, the effect of depletion was counteracted by replacement injections of epinephrine, and responding was increased above control levels in intact subjects injected with epinephrine — all in a single experiment. The only previous study to find both a reduction of responding to an an aversive stimulus resulting from adrenal demedullation and an attenuation of this effect with replacement epinephrine (Conner & Levine, 1969) did not find that injection of epinephrine enhanced reponding in intact subjects. Experiment 4 constitutes the only within-experiment demonstration of an enhancement of responding to an aversive stimulus by a low dose of epinephrine and a disruption of this responding by a high dose of epinephrine. Gupta and Holland (1969) might have found a similar effect (see Table 1), but because the appropriate statistical comparison was not made in their multiple factorial design, it is impossible to tell whether their lowest dose significantly enhanced two-way active avoidance responding. Reasons for the Popularity of Conditioned Active Avoidance Paradigms In light of the success of studies of the relationship between epinephrine and innate reponses to aversive stimuli, the 54 concentration by experimenters on conditioned active avoidance paradigms (cf. Tables 1 and 2) might seem paradoxical. Because the conditioned active avoidance paradigms have been the most prevalent means of studying epinephrine-behaviour relations it is important to be aware of the reason why they have been employed. An examination of the introductions to relevant studies suggests that two factors have contributed to the prevalence of the conditioned active avoidance paradigm: 1) the results of studies in which epinephrine was injected to humans suggested that epinephrine affected emotions and emotional behaviour and, 2) Mowrer's (Mowrer & Lamoureaux, 1946; Mowrer, 1947) popular theory of active avoidance conditioning suggested that fear was an important intervening variable in the acquisition of an active avoidance response. These two factors will be discussed below under appropriate headings, and in a subsequent section, a reason why active avoidance paradigms might not have been particularly successful in demonstrating a relationship between epinephrine levels and responding in aversive situations will be proferred. Effect of Epinephrine Injections on Human Behaviour Prior to, and concomitant with, the early studies of the relationship between epinephrine and aversive responding in rats were a number of studies examining the relationship between epinephrine and emotional behaviour in humans. The early researchers (e.g. Cantril & Hunt, 1932; Landis & Hunt, 1932) found that accompanying the autonomic arousal produced by injected epinephrine were what Maranon (1924) labelled "cold emotions". For the most part, the human subjects did not report 55 feeling genuine emotions but said, for example, that they felt "as if" they were afraid or anxious. The occasional subject, however, did report experiencing a genuine emotion when epinephrine was injected (Cantril & Hunt, 1932). Subsequently, Cantril (1934) found that if an emotion-producing stimulus (e.g., a sudden loud noise) was also applied in the experimental situation, the subjects reported experiencing genuine emotional states (e.g., fear) more intense than those experienced by control subjects injected with a placebo. In 1962, Schachter and his associates (Schachter & Singer, 1962; Schachter _ Wheeler, 1962) performed a series of experiments, the results of which appeared to clarify and extend the findings of the earlier experiments (Leshner, 1978; Smith, 1973). Schachter and his colleagues demonstrated that it was possible to enhance the behaviour reflecting emotional states with systemic injections of epinephrine, provided that the appropriate environmental stimuli were present. For example, injected epinephrine was found to produce a two-fold increase in the anger-related behaviour of male students unaware of the nature of the injection, when they were required to fill out an irritating questionnaire and another person in the same room was acting angry (Schachter & Singer, 1962). In addition, Schachter found that the environmental manipulations and not the injected epinephrine appeared to determine what type of emotion the subject felt. For example, injected epinephrine was found to also increase the amount of amusement felt by subjects watching a slapstick comedy film (Schachter & Wheeler, 1962). Schachter concluded that emotion is a joint product of physiological 56 arousal and situational cues. Schachter's hypothesis has since been tested in two other published experiments in which epinephrine was administered systemically. Rogers and Deckner (1975) failed to confirm Schachter's conclusions. They found that reports of subjective fear by people who smoked cigarettes were increased by injecting epinephrine, watching a film about cancer, or a combination of both treatments; however, the amount of subjective fear reported by these different groups of subjects did not differ significantly. According to Gerdes (1979), it is possible that the subjects watching the film had a sufficiently high level of endogenous epinephrine to render the injected epinephrine superfluous. In 1979, Gerdes reported findings which were compatible with Schachter's hypothesis. She found that subjects injected with epinephrine while they were waiting for oral surgery reported greater fear than subjects who were not given this hormone, provided that the subjects injected with epinephrine did not know that epinephrine had been administered. If these subjects were informed that they should expect some symptoms of autonomic arousal, they did not report more fear than did the subjects not injected with epinephrine. Although not conclusive, these studies suggest that epinephrine injections may enhance emotional behaviour exhibited by human subjects in emotional situations. Mowrer's Theory of Avoidance Conditioning In the late forties, Mowrer (Mowrer, 1947; Mowrer & Lamoureaux, 1946) postulated that conditioned fear is a critical 57 factor in the production of avoidance responding. According to Mowrer, it was the reduction of the fear conditioned to the conditioned stimulus that reinforced the avoidance response. Moreover, this fear state was supposedly mediated by the underlying actions of the autonomic nervous system. Thus, Mowrer himself predicted that epinephrine levels would influence conditioned active avoidance behaviour (Smith, 1973). Because the experiments performed on humans had suggested that epinephrine might affect the emotions and emotional behaviour exhibited in aversive situations and because Mowrer's theoretical explanation of avoidance responding implicated both epinephrine and an emotional response, it is not surprising that many early investigators wishing to study the relationship between epinephrine and behaviour would decide to utilize the conditioned active avoidance paradigm, the same paradigm used by Mowrer as a basis for developing his theory. In many cases, more recent researchers seem to have used the same paradigm without considering its merits. Why Active Avoidance Paradigms Have Not Been Successful At a superficial level investigators using conditioned active avoidance paradigms were merely trying to answer the following question: What is the relationship between epinephrine and fear-mediated behaviour? In doing so, however, they were making questionable assumptions. First they assumed, that ^Mowrer's theoretical interpretation of conditioned avoidance was correct; that is, that avoidance learning is dependent upon an emotional response being elicited by the conditioned aversive stimulus. Second, they assumed that an increase in the intensity 58 of this emotional response would facilitate avoidance conditioning (cf. Moyer & Bunnell, 1958). Even if the controversial first assumption (Herrnstein, 1969; Mackintosh, 1974; Tarpy, 1975) were accepted, a number of reasons can be generated for questioning the second assumption (Moran, Ahmad, & Meagher, 1970). For example, increasing shock intensity has been found to result in increased epinephrine release from the adrenal medulla (Frankenhaeuser, 1971; Frankenhaeuser, Frohber, & Mellis, 1965/66), yet shocks of high intensities have been found to interfere with the acquisition of two-way active avoidance responses (Mackintosh, 1974; Tarpy, 1975). In the two-way active avoidance paradigm crouching and freezing are, initially at least, the prepotent responses (e.g., Anisman & Walhsten, 1974). It has been suggested by many authors (e.g., Moyer & Korn, 1964; Mackintosh, 1974; Tarpy, 1975; Theios, Lynch, & Lowe, 1966) that high shock levels retard two-way active avoidance performance by enhancing these crouching and freezing responses that compete with the required avoidance response. It is possible that epinephrine itself could be one of the factors mediating the disruptive effect of high shock levels. Increased shock intensity could increase endogenous epinephrine levels which in turn could enhance crouching and freezing. Thus, in some situations one might expect a disruption, rather than a facilitation of active avoidance in response to increasing levels of emotionality. Conclusion The point made in the preceding section is merely a reason why injections of epinephrine might not necessarily be expected 59 to enhance conditioned active avoidance responses and not a claim that systemic epinephrine does not enhance learned responding in aversive situations. Although many studies have examined the effect of altering peripheral epinephrine levels on learned responses to aversive stimulation, the results of these studies have been so inconsistent that it is impossible to tell whether systemic epinephrine enhances learned reponding or not. The results of the present studies, however, clearly confirm the hypothesis that systemic epinephrine enhances innate responding in aversive situations. 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