Pituitary-Adrenal Influences on Avoidance and Approach Behavior of the Rat

Pituitary-Adrenal Influences on Avoidance and Approach Behavior of the Rat BELA BOHUS Rudolf Magnus Institute for Pharmacology, Medical Faculty, University of Utrecht, Vondellaari 6, Utrecht (The Netherlands)

It is well established that the pituitary-adrenal system plays an essential role in the organism’s adaptive reactions towards Environmental stimuli. Beside physical somatic factors, neurogenic or emotional stimuli such as anxiety or fear invariably induce the discharge of corticotrophin (ACTH) from the adenohypophysis and the subsequent increase in the production of adrenal corticosteroids. Although several aspects of socalled stress-induced pituitary-adrenal activation have been explored in relation to the “peripheral” mechanisms of adaptation, relatively little attention has been paid to studying the brain as a possible target organ for these hormones. In the course of clinical assessment of adrenocortical steroids and ACTH as therapeutic agents, it was frequently noticed that a number of psychological changes, including mood alterations and disturbance, occurred. Excitability changes in seizure threshold, as observed clinically, were also observed in animals after administration of ACTH or corticosteroid. The experimental studies on the role of pituitary-adrenal hormones in behavioral adaptation took their origin from very different starting points. For example, my studies were primarily stimulated by the recognition of the involvement of discrete brain regions in the “feedback” effect of steroids on the release of pituitary ACTH (Bohus et al., 1968a). De Wied’s interest originated from observations in posterior lobectomized rats showing impaired ACTH release to emotional but not to somatic stimuli (De Wied, 1969). Certain relationships between the performance of avoidance behavior and pituitary-adrenal responsiveness also stimulated several groups to study the behavioral influence of these hormones (Lissak and Endroczi, 1964; Levine, 1968; Weiss et al., 1970). Recently a number of observations on this subject indicate that the behavioral effects of these hormones are now well established. The aim of this paper is to summarize our knowledge on the behavioral effects of pituitary and adrenal hormones with special attention to the mode, the site and the specificity of their actions on central nervous mechanisms. Several aspects of the influence of pituitary-adrenal hormones on avoidance behavior of rodents were studied by us and by other groups. Acquisition of active avoidance response is markedly impaired by hypophysectomy (Applezweig and Baudry, 1955; Applezweig and Moeller, 1959; De Wied, 1964). Administration of References P . 418-419

408

B. BOHUS

ACTH-like peptides reverses the learning deficit of the operated rats. Response performance of hypophysectomized rats can also be restored by supplementary treatment with thyroxine, cortisone and testosterone (De Wied, 1964) or by growth hormone (De Wied, 1969). Accordingly, metabolic factors are important in the impaired learning capacity of hypophysectomized rats. However, normalizing the acquisition rate by pituitary peptides is independent of a metabolic effect and not mediated by the adrenal cortex as was demonstrated by using peptides structurally related to ACTH but devoid of corticotrophic and anabolic activities (De Wied, 1969). The influence of ACTH-like peptides depends on the actual presence of the peptide. Daily administration of ACTH,-, , improves the acquisition of a shuttlebox avoidance response in hypophysectomized rats. Cessation of the treatment results in a gradual impairment of avoidance performance (Bohus et a/., 1973). While the removal of the pituitary markedly influences avoidance acquisition, adrenalectomy has no substantial effect on it, i.e. acquisition of active avoidance can take place in the absence of corticosteroids. Slight improvement of shuttle-box avoidance performance as observed by Beatty et al. (1970) and Weiss et al. (1970) is presumably due to the increase in release of pituitary ACTH in adrenalectomized rats. Slight temporary facilitation of active avoidance acquisition was observed in intact rats after administration of ACTH. This influence, which appeared also to be present in the absence of the adrenals, depended on a certain development of conditioned behavior (Bohus and Endroczi, 1965; Bohus et al., 1968b). Extinction of active avoidance behavior appeared to be substantially affected by alteration of pituitary-adrenal function. Administration of ACTH results in a delay of extinction. This effect also appeared to be extra-adrenal; the peptide is effective in adrenalectomized rats as well (Miller and Ogawa, 1962; Bohus et al., 1968b). Corticosteroids on the other hand seemed to affect the extinction rate of active avoidance response in an opposite way: enhancement of extinction was observed not only with corticosterone, which is the physiological glucocorticoid of the rat, but with cortisone and dexamethasone as well (De Wied, 1967; Bohus and Lisssik, 1968). It was also shown that this effect of steroids is not closely related to the glucocorticoid activity, since other steroids such as pregnenolone and progesterone but not testosterone and estradiol were equipotently active (Van Wimersma Greidanus, 1970). These first results on the effect of pituitary-adrenal hormones stimulated at least two major directions in further research. The extra-adrenal nature of ACTH on the function of the central nervous systems raised the question as to whether the full peptide molecule is essential for the behavioral effects. A series of experiments in De Wied’s laboratory clearly demonstrated that even the heptapeptide ACTH,,, has full behavioral activity in avoidance responding (De Wied, 1966, 1969; De Wied et al., 1968). More details and recent developments on this line of research are described by Greven and De Wied in this volume (p. 429-442). The other line of research has attempted to explore the site of action of pituitaryadrenal hormones in the brain. The first suggestion of the involvement of the thalamic parafascicular region in the mediation of peptide effects on avoidance extinction was given by experiments in rats bearing mid-posterior thalamic lesions. Melanocyte-

ACTH, STEROIDS, BEHAVIORAL

AND AUTONOMIC RESPONSES

409

stimulating hormone (a-MSH, acetyl-ACTHI-, 3 ) in amounts which in intact rats increase resistance to extinction, failed to delay the rapid extinction of a shuttle-box avoidance response in rats with bilateral lesions in the parafascicular area (Bohus and De Wied, 1967).Subsequent experiments withintracerebral implantation of ACTH,-,, extended this observation: the extinction of a pole-jumping avoidance response is delayed in rats when the peptide is implanted in the parafascicular area of the thalamus (Van Wimersma Greidanus and De Wied, 1971). Jntracerebral implantation of various steroids revealed the importance of this thalamic area as one site of action of corticosteroids on avoidance extinction. Corticosteroids implanted in the parafascicular nuclei of the thalamus or in the rostra1 mesencephalic reticular formation enhance the extinction of active avoidance response (Bohus, 1968; Van Wimersma Greidanus and De Wied, 1969; Bohus, 1970a). It has also been demonstrated that the opposite behavioral effect of ACTH and steroids involves their action on the thalamic area. The stronger the suppression of avoidance performance by intrathalamic steroid implants, the larger the amount of ACTH necessary to prevent the steroid action (Bohus, 1970b). In the meantime it was shown that corticosteroids may also act through forebrain mechanisms. Cortisone implanted in the anterior hypothalamus, septum, amygdala or dorsal hippocampus of the rat enhances the extinction of an active avoidance response (Bohus, 1970a). These observations were in favor of previous suggestions based upon both behavioral and electrophysiological experiments (Lissik and Endroczi, 1964; Bohus and Endroczi, 1965; Endroczi, 1969) in which corticosteroids enhanced forebrain-inhibitory processes, thus leading to enhanced internal inhibition. The suppressive influence on the ascending reticular function and the enhancement of forebrain inhibition by steroids presupposed a dual character of their behavioral action (Bohus, 1971). Facilitation of active avoidance extinction may be interpreted as a synergistic influence of steroids on both systems. One might then expect that the effect of steroids on passive avoidance behavior based upon the inhibition of a motivated response may have even an antagonistic-like action on the two systems unless the enhancement of forebrain inhibition by hormones has a suppressive effect on fear motivation rather than on the performance. Corticosteroids such as cortisone or dexamethasone suppress passive avoidance responses in both aversive )IS. aversive and thirst vs. fear conflict situations. Suppression of passive avoidance depended on the shock-intensity and the dose of cortisone administered before learning in an aversive vs. aversive situation (Bohus et d.,1970a). Corticosterone, the main glucocorticoid of the rat adrenal cortex, and glucocorticoids such as cortisol were also effective if the passive avoidance behavior of rats was investigated in a thirst vs. fear conflict situation. The experimental paradigm has been described in detail elsewhere (Bohus, 1971). Suppression of passive avoidance immediately after the shock trial and 24 h later was seen when high doses of corticosterone, cortisol or 6-dehydro-l6-methylene-cortisolwere given before the learning trial. The lower doses of steroids were ineffective except for corticosterone 24 h after the learning trial. Deoxycorticosterone was not effective even at a high dose level (Fig. 1). The ACTH suppressive potency of these steroids was also determined by References p . 418-419

410

B. BOHUS median avoidance Latency(sec)

median avoidance Latency (sec)

,300

i

6-dh-16-m-cortisol Olmg doc 5 0 m g cortisol 02 mg

60.

I

50

\

1200

I

\ cwticosterone

1

10

20 h 0 RETENTION

30

LO 50 10 20 in vitro corticostwoid production ug/100mg adrenoL/h

in ma

1

6 dh-16 -m - tort-isd Q5 mg

30

LO

50

24

RETENTION

Fig. I . The influence of naturally occurring and synthetic adrenal steroids on the retention of a passive avoidance response in a thirst vs. fear conflict situation and on the activation of pituitaryadrenal system accompanying the behavioral situation. Steroids were given S.C. 2 h before the single shock trial. In vitro corticosteroid production of the adrenals served as an index of pituitary ACTHrelease. Each point represents 8-10 observations. doc, deoxycorticosterone; 6-dh-16-m-cortisol, 6-dehydro-16-methylene-cortisol.

measuring the corticosteroid production of the adrenals in vitro 15 min after the immediate and 24-h trials. ACTH release was suppressed by high doses of cortisol and 6-dehydro-16-methylene-cortisol. The behavioral effect of this latter steroid was positively correlated with the endocrine influence: the stronger the suppression of ACTH release induced by the behavioral stress, the more effective was the suppression of behavior. As far as the locus of action of these steroids is concerned, corticosterone implants both in the forebrain and the medial thalamus were effective in suppressing passive avoidance in the 24-h retention test, whereas forebrain implants were effective in suppressing immediate passive avoidance as well. Cortisol suppressed passive avoidance both in immediate and 24-h retention tests whenever the implants were located in the forebrain or the medial thalamus. 6-Dehydro-16-methylene-cortisoland deoxycorticosteroid implants in general were ineffective (Fig. 2). The former steroid is known as a potent blocker of ACTH release which presumably acts at lower hypothalamic sites and at the pituitary level (Berthold et al., 1970). Therefore, it seems that suppression of passive avoidance by systemic administration of this steroid is due to suppression of ACTH release. Indeed, ACTHP,-,, administered before the single learning trial enhanced passive avoidance retention if the shock intensity is mild. Hypophysectomy, on the other hand, suppresses the avoidance behavior. These

ACTH, STEROIDS, BEHAVIORAL

111 h n i n l l l

A U W D M LATENCY (percent of controls)

MEDW THMAMUS

120

LO

41 1

AND AUTONOMIC RESPONSES RTUITAR%PDRENAL

~CTNITY (percent of cmtmlr)

LO

ill

ANTERIOR HYPOTHALAMUS

12

WRSL HIPPOCAMPUS 1120

, - --, ~ ~ SEPTUM

1201

1120

li/i[l , - , n l ~ n l [ FRONTAL CORTEX

LO

Oh

2Lh

retentm CORTICOSTERONE

PA

act

Oh

2Lh

retention

P-A cct

6-DEHYDRO-16 -METHYLCORTISOL

Oh

2Lh

retentm CORTISOL

1120

60

LO

P-A act

Oh

2Lh retenhm

P-A oct

DEOXYCORTICOSTERCNE

Fig. 2. The effect of intracerebral implantation of various crystalline steroids on the retention of a passive avoidance response in a thirst vs. fear conflict situation and on pituitary-adrenal activity as measured by the in vitro corticosteroid production of the adrenals determined 15 min after the retention test at 24 h. The steroids were implanted one day before the single avoidance learning trial. The stars on top of the columns represent the level of significance (West). 8-10 observations per placement and per steroid. *, p > 0.05, **, p > 0.01.

effects also depend on the shock intensity (Lissa'k and Bohus, 1972). Observations of Levine and Jones (1965), Weiss et al. (1970) and Guth et al. (1971a) are in agreement with these findings. If one summarizes the behavioral studies in active and passive avoidance situations, the most parsimonious explanation for the effect of ACTH, ACTH-like peptides and corticosteroids seems to be an influence on the fear level which motivates avoidance behavior. The magnitude of the effects appeared to be a function of the drive intensity and the dose of hormones applied. The higher the drive intensity, the less the References p , 418-419

412

B. BOHUS

modification of the behavior. Although the insensitivity of behavioral measures in certain situations cannot be totally excluded, it seems reasonable to postulate that the central nervous system is less sensitive to hormonal effects when the aversive stimuli evoke high drive-intensity levels. A clear dichotomy appears between the behavioral and endocrine feedback effects of most of the steroids. Thus, the primary behavioral influence of steroids is not mediated through the suppression of ACTH release. As far as the mode of action of pituitary-adrenal hormones is concerned, enhancement of internal inhibitory processes by corticosteroids leading to the suppression of fear has been suggested (Bohus and Lissik, 1968). Based upon intracerebral implantation and electrophysiological experiments, this hypothesis was reinforced (Bohus, 1970a), but, in addition, the observation that the steroids affect avoidance behavior through ascending reticular structures at the mesencephalic and thalamic level as well (Bohus, 1968, 1970a; Van Wimersma Greidanus and De Wied, 1969) suggests a “dual character” of steroid action on the brain. However, as shown earlier, the behavioral consequences of this “dual character” were not apparent in passive avoidance situations. Facilitation of forebrain activity results in enhanced passive avoidance. Corticosteroid implants in the forebrain, however, suppressed passive avoidance. Therefore, it is more likely that the influence of corticosteroids on forebrain mechanisms always bears a suppressive property on aversively motivated behavior. Factors such as increased thirst drive in a conflict situation or impairment of pain perception in passive avoidance experiments may play a certain role in the effect of steroids on behavior. Meanwhile, the fact that the steroids affect immediate passive avoidance behavior suggests that attenuation of motivational influence may be the mode of action of these hormones. In order to decide whether a motivational hypothesis is valid, two further directions of research were introduced: ( I ) the study of autonomic responses evoked by the emotional stimuli and (2) the behavioral analysis of pituitary-adrenal system hormones in situations motivated by factors other than aversion. There exists increasing evidence from psychophysiological literature for the occurrence of marked autonomic response changes in relation to the emotional status of an animal. One of the most significant systems responding to environmental and internal stimuli is the cardiovascular system. Psychological stresses such as fear or anxiety elicit marked alterations in heart rate, blood pressure, blood flow, etc. These responses may be of both behaviorally and metabolically relevant changes accompanying the psychological and somatic events during behavioral adaptation (Obrist et al., 1970). Several observations suggest that both classical and instrumental conditioning may occur in the autonomic nervous system (Razran, 1961; Miller, 1969) and that both of these influences may affect the emotional state of the animals. Since it was not clear how ACTH-like peptides and corticosteroids affect these processes, the following experiments were carried out. Experiments in a classically conditioned fear situation showed that both ACTH and corticosteroids influence the heart rate of rats used as a psychophysiological measure (Bohus et al., 1970b, 1971). When ACTH4-,, and corticosterone were given during the extinction of classically conditioned fear, significant alterations of brady-

ACTH, STEROIDS,

BEHAVIORAL A N D AUTONOMIC RESPONSES

413

mean interbeat interval per 5 sec in msec

m

A1

2

3 El2

pre-st imulus

3

treatment

2

3

2

3

conditioned stimulus interval

Al 2

3

2

3 days

post-stimulus

Fig. 3. The effect of ACrH4-10 and corticosterone treatment given during the extinction period on the heart rate of rats in a classically conditioned fear situation. Each point represents the mean of 3 non-reinforced trials during acquisition (A) or 12 extinction (E) trials. Heart rate was analysed for 5-5-5 sec, before (pre-stimulus interval), during (conditioned-stimulus interval) and after (poststimulus interval) the presentation of the conditioned stimulus in each trial.

cardiac heart rate response, as developed during acquisition, occurred. As a consequence of ACTH,-,, treatment an increase in heart rate developed, whereas corticosterone resulted in a decrement of cardiac rate during fear extinction. However, these treatment effects were not restricted to the conditioned cardiac response. Similar patterns of heart rate changes appeared in the pre- and post-stimulus intervals (Fig. 3). That is to say, pituitary-adrenal hormones influenced the autonomic consequence of generalized emotional responses of rats which typically developed after this type of classical conditioning. The development of an off-line computer measurement of interbeat interval time allowed a more precise insight into the hormonal effects on conditional cardiac responses. The conditioned heart rate response appeared in a gradually developing bradycardia during the presentation of the conditioned stimulus. The effect of the first 12 extinction trials in control rats is a less pronounced conditioned response. However, both corticosterone and ACTH,-,,-treated rats showed the response during these trials. The conditioned response was not present after the next 12 extinction trials in control and corticosterone-treated rats, whereas the bradycardiac conditioned response was still marked in rats with ACTH4-lo treatment. Continuation of extinction tended to increase the heart rate in response to the conditioned stimulus. This shift in conditioned response was the most pronounced in ACTH,-,,-treated rats (Fig. 4). These experiments again strongly suggest the opposite effects of ACTH-like peptides and corticosteroids on a response other than behavioral to aversive conditioning. Further, the hormones seemed to affect both the general emotional status and the conditioned response. The rapid disappearance of bradycardiac heart rate changes in ACTH-treated rats seems to indicate that the generalized autonomic response to classical conditioning has been rapidly extinguished, but, at the same time, References p . 418-419

414

B. BOHUS n HEART RATE b.oh/min

.. . .

bcotshin

p a

.

....

9

ollOdU%sU

I . .. , ..

o HEmT RATE

I

.

.

.

SnLw

cs

post-cs

CORTICOSTERONE

+I51

I

I-56 7

8

9 ~ I l T 2 B Y 61-55 7

8

cs 15t

post-cs pMs

cs

.

9 lOllQBUl5+56 J

p.cs

post-cr p a

2nd EXTINCTION SESSON

7

8 cs

post-cs

3rd

Fig. 4. The effect of ACTH4-in and corticosterone treatment on a conditioned cardiac response during the extinction of classically conditioned fear. Heart rate was calculated from the mean cardiac frequencies of each second of the presentation of the conditioned stimulus minus the mean heart rate for 5 sec before the trial. The differences between the post-stimulus and pre-stimulus heart rate are also given. cs, conditioned stimulus.

the conditioned cardiovascular consequence of fear conditioning is well preserved in peptide-treated rats. The opposite seems to hold for corticosterone-treated rats. If one assumes that emotionality changes, or increase in the level of general arousal, are accompanied by heart rate increase, these preliminary observations are in favor of an effect of hormones on arousal of certain structures in the central nervous system enhancing or attenuating the motivational effect of environmental stimuli. If one speaks about effects on arousal or motivation, the question immediately arises whether such influences are only related to aversive motives or whether one should expect hormonal influences on approach motives as well. Data are accumulating that pituitary-adrenocortical hormones may affect the acquisition and extinction of appetite and drinking responses (Bohus, 1971; Gray, 1971; Gray et al., 1971; Guth et al., 1971b; Sandman et al., 1969). However, negative observations by Weijnen and Slangen (1970) have also been published. In order to observe any influence of pituitary-adrenal hormones on approach behavior, the importance of stringent

ACT&

STEROIDS, BEHAWORAL AND AUTONOMlC RESPONSES

415

C R‘s treatment

h

6t

2

L

23h deprivation:

*=

6

8

10

12

1L days

~f~~~{~terone

12h deprivation: o---a corticosterme 0-4

placebo

Fig. 5. The effect of corticosterone treatment (1.0 mg/100 g body weight) on the acquisition of a space-discriminativeconditioned drinking response as a function of the deprivation time. Each point represents the mean of 8 observations. CR, conditioned response.

controls for extraneous noise and level of motivation (Guth et al., 1971b) and of conflict components in the experimental situation (Bohus, 1971) has been suggested. The following experiments are in favor of these suggestions. The influence of corticosterone treatment on acquisition of a space-discriminative conditional drinking response is a function of the deprivation level, and consequently of the drive intensity. The acquisition rate was not affected by the treatment if the rats were kept on a 23-h deprivation schedule. However, a marked retardation of the acquisition of the conditioned response was observed in corticosterone-treated rats kept on a 12-h water deprivation (Fig. 5). Further experiments demonstrated that corticosterone markedly affected the conditioned response performance in a signal-discriminative drinking situationtowards both the reinforced and non-reinforced stimulus, if the steroid was administered during reversal training. Corticosterone-treated rats exhibited an enhanced reversal: the response rate was accelerated to the new reinforced stimulus, while the nonreinforced responses were rapidly extinguished (Fig. 6 ) . Similar effects of cortisone have been described previously (Bohus, 1971). The significance of a conflict component in the behavioral effects of pituitary-adrenal system hormones as shown by this observation is supported by experiments involving “frustrative non-reward”. ACTH administration can block the effect of frustrative non-reward during partial reinforcement acquisition or extinction of appetite responses (Gray et a/., 1971; Gray, 1971). The present experiments and the observations of Sandman et al. (1969), Gray (1971), Gray et al. (1971) and Guth et al. (1971b) indicate that ACTH, ACTH-like peptides and corticosteroids have opposite effects on approach behavior as well. Furthermore, the reversal learning data suggest that the attenuation of the response by corticosteroids is not a general property of these hormones. One should not forget References P. 418-419

416

B. BOHUS

100-

80. 60-

LOM-

treatment

non-reinforced

L saline

60

LO 20-

I

cwticosterone

I

I

3 2

I

1

1

2

3

b

5

6

7

8

9 1 0 1 1 l 2 days

Fig. 6. The effect of corticosterone treatment on the reversal of a signal-discriminativeconditioned drinking response. 8-8 observations per point. CR, conditioned response.

that the conditioning procedure employed in these experiments is complex. The original discriminative learning involves the acquisition of the ability to respond towards the reinforced stimulus and to eliminate the motivational property of this stimulus if another signal is also present and not followed by reinforcement. During the reversal training the animal must learn against the background of a well-conditioned inhibitory mechanism and, at the same time, must eliminate the previously reinforced conditioned response. Therefore, it seems that corticosteroids are not only able to eliminate the non-reinforced response by suppressing the motivational value of the conditional stimulus, but are also capable of suppressing the inhibitory value of the previously non-reinforced signal, thus resulting in an enhanced reversal acquisition. On the basis of this experiment with steroid and other studies with ACTH in approach conditioning one would expect an opposite effect of ACTH or ACTH-like peptides on reversal learning.

ACTH,

STEROIDS, BEHAVIORAL AND AUTONOMIC RESPONSES

417

GENERAL CONCLUSIONS

Although a large number of observations has been collected by us and by others concerning the behavioral effects of pituitary-adrenal hormones, it is still not easy to draw a conclusion on the mode of action of these hormones. It is clear that both pituitary ACTH or ACTH-like peptides and corticosteroids profoundly influence adaptive behavior whether it is motivated by aversive or by approach motives. Furthermore, it is also well established that the peptides and steroids affect adaptive responses of either behavioral or autonomic nature in an opposite manner. The mode of action of pituitary-adrenal hormones may be described in terms of an increase or attenuation of the motivational property of diffuse and specific conditioned environmental cues. Such an influence may be due to a general influence of the excitability of the brain. However, studies that attempted to locate the action of both the peptide and steroid effect in the brain suggest that their influence is restricted to those systems that are involved in the integration of incoming extero- and interoceptive stimuli and/or in motivational processes. Dependence of their effects on drive intensity seems in favor of a motivational hypothesis rather than a non-specific generalized arousal. Attenuation of the motivational property of external and internal stimuli by ACTH and corticosteroids as a rather specific influence in relation to the pituitaryadrenal responsiveness to specific behavioral stressor stimuli is still obscure. However, a certain specificity, at least concerning the mode of action of ACTH or ACTHlike peptides, is suggested by observations showing faciiitation of avoidance learning in intact rats if a certain number of avoidance responses has appeared (Bohus et al., 1968b). This observation suggests that enhancement of the association of environmental signals with the motivational factors may also be responsible for some of the behavioral effects of pituitary-adrenal hormones. Increased ability to detect sensory signals of auditory, gustatory and olfactory modalities by patients after removal of all adrenocortical hormone activity, and decreased sensory detection in patients with excessive glucocorticoid secretion as observed by Henkin (1970), seem to support this assumption. However, if pituitary-adrenal hormones affect associative processes, this influence appears to be limited to the presence of peptides or steroids, since the behavioral changes observed are not seen after the cessation of treatment. For this reason, it is unlikely that permanent associative processes related to learning and memory are affected by pituitary-adrenal hormones. In conclusion, it is suggested that these hormones attenuate or facilitate the motivational property of both conditioned and unconditioned stimuli.

SUMMARY

Pituitary-adrenal system hormones markedly influence adaptive responses of behavioral and autonomic nature. The behavioral effects are present whether a response is motivated by aversive or approach motives. The peptides and steroids have opposite References p . 418419

41 8

B. BOHUS

effects on adaptive responses. The mode of action of pituitary-adrenal system hormones may be described in terms of an increase or attenuation of the motivational properties of environmental and internal bodily stimuli. The sites of action of hormones are located in the brain stem and the forebrain.

ACKNOWLEDGEMENTS

The author is greatly indebted to Organon Comp., Oss, The Netherlands, for supplying the steroids, ACTH and ACTH analogs. The generous donation of 6-dehydro-16methylene-cortisol by Merck Comp., Darmstadt, Germany, is also acknowledged. REFERENCES

APPLEZWEIG, M. H. AND BAUDRY, F. D. (1955) The pituitary adrenocortical system in avoidance learning. Psychol. Rev., 1, 417-420. APPLEZWEIG, M. H. AND MOELLER, G. (1959) Anxiety, the pituitary-adrenocortical system and avoidance learning. Acta psychol., 15, 602-603. BEATTY,P. A., BEATTY, W. W., BOWMAN, R. E. AND GILCHRIST, J. 0. (1970) The effects of ACTH, adrenalectomy and dexamethasone on the acquisition of an avoidance response in rats. Physiol. Behav., 5, 939-944. BERTHOLD, K., ARIMURA, A. AND SCHALLY, A. V. (1970) In vivo studies on the mechanism of action of 6-dehydro-l6-methylene-hydrocortisone(STC 407) on the hypothalamo-pituitary-adrenal axis in rats. Neuroendocrinology, 6, 301-310. BOHUS,B. (1968) Pituitary ACTH release and avoidance behavior of rats with cortisol implants in mesencephalic reticular formation and median eminence. Neuroendocrinology, 3, 355-365. BOHUS,B. (1970a) Central nervous structures and the effect of ACTH andcorticosteroids on avoidance behavior: A study with intracerebral implantation of corticosteroids in the rat. In Pituitary, Adrenal and the Brain (Progress in Brain Research, Vol. 32), D. DE WIEDAND J. A. W. M. WEIJNEN (Eds.), Elsevier, Amsterdam, pp. 171-184. BOHUS,B. (1970b) The medial thalamus and the opposite effect of corticosteroids and adrenocorticotrophic hormone on avoidance extinction in the rat. Acta physiol. acad. sci. hung., 38, 217223. BOHUS,B. (1971) Adrenocortical hormones and central nervous function: the site and mode of their behavioral action in the rat. Proc. Second Int. Congr. Hormonal Steroids. Excerpta med. int. Congr. Series, No. 219,752-758. B o ~ u s ,B. AND ENDROCZI,E. (1965) The influence of pituitary-adrenocortical function on the avoiding conditioned reflex activity in rats. Acta physwl. acad. sci. hung., 26, 183-189. BOHW,B. AND DEWIED,D. (1967) Failure of a-MSH to delay extinction of conditioned avoidance behavior in rats with lesions in the parafascicular nuclei of the thalamus. Physiol. Behav., 2,221-223. Bo~us,B. AND LISSAK,K. (1968) Adrenocortical hormones and avoidance behavior in rats. Znt. J . Neuropharmacol., 7 , 301-306. BOHUS,B., NYAKAS,C. AND LISSAK,K. (1968a) Involvement of suprahypothalamic structures in the hormonal feedback action of corticosteroids. Acta physiol. acad. xi.hung., 34, 1-8. BOHUS,B., NYAKAS, C. AND ENDROCZI,E. (1968b) Effects of adrenocorticotropic hormone on avoidance behavior of intact and adrenalectomized rats. Int. J . Neuropharmacol., 7 , 307-314. BOHUS,B., GRUBITS,J., KovAcs, G. AND LISS~K, K. (1970a) Effect of corticosteroids on passive avoidance behavior of rats. Acta physiol. acad. sci. hung., 38, 381-391. BOHUS,B., GRUBITS,J. AND LISSAK,K. (1970b) Influence of cortisone on heart rate during fear extinction in the rat. Acta physiol. acad. sci. hung., 37, 265-272. BOHUS,B., DE WIED,D. AND LISSAK,K. (1971) Heart rate changes during fear extinction in rats treated with pituitary peptides or corticosteroids. Proc. 25th Int. Congr. Inr. Union Physiol. Sci., Vol. IX, p. 72.

ACTH, STEROIDS,

BEHAVIORAL AND AUTONOMIC RESPONSES

419

BOHUS, B., GISPEN,W. H. ASD DE WIED,D. (1973) Effect of lysine vasopressin and ACTH 4-10 on conditioned avoidance behavior of hypophysectomized rats. Neuroendocrinology, 11, 137-143. DE WIED,D. (1964) Influence of anterior pituitary on avoidance learning and escape behavior. Amer. J. Physiol., 207, 255-259. DE WIED,D. (1966) Inhibitory effect of ACTH and related peptides on extinction of conditioned avoidance behavior in rats. Proc. SOC.exp. Biol. ( N . Y . ) , 122, 28-32. DEWIED,D. (1967) Opposite effects of ACTH and glucocorticosteroids on extinction of conditioned avoidance behavior. Excerpt4 med. int. Congr. Series, No. 132, 945-951. DE WIED,D. (1969) Effects of peptide hormones on behavior. In Frontiers in Neuroendocrinology, W. F. GANONG AND L. MARTINI (Eds.), Oxford University Press, New York, pp. 97-140. DE WIED,D., BOHUS,B. AND GREVEN, H. M. (1968) Influence of pituitary and adrenocortical hormones on conditioned avoidance behavior in rats. In Endocrinology and Human Behavior, R. P. MICHAEL (Ed.), Oxford University Press, New York, pp. 188-199. ENDR~CZI, E. (1969) Brain stem and hypothalamic substrate of motivated behavior. In Results in Neurophysiology, Neuroendocrinology, Neuropharmacology and Behavior (Recent Developments of Neurobiology in Hungary, Vol. II), K. LISSAK(Ed.), Hung. Acad. Sci., Budapest, pp. 2 7 4 9 . GRAY,J. A. (1971) Effect of ACTH on extinction of rewarded behavior is blocked by previous administration of ACTH. Nature, 229, 52-54. GRAY,J. A., MAYES, A. R. AND WILSON,M. (1971) A barbiturate-like effect of adrenocorticotrophic hormone on the partial reinforcement acquisition and extinction effects. Neuropharmacology, 10, 223-230. GUTH,s., SEWARD, J. P. AND LEVINE,S. (1971a) Differential manipulation of passive avoidance by exogenous ACTH. Hormones Behav., 2, 127-138. GUTH, S., LEVINE,S. AND SEWARD, J. P. (1971b) Appetitive acquisition and extinction effects with exogenous ACTH. Physiol. Behav., 7, 195-200. HENKIN,R. I. (1970) The effects of corticosteroids and ACTH on sensory systems. In Pituitary, Adrenal and the Brain (Progress in Brain Research, Vol. 32), D. DE WIEDAND J. A. W. M. WEIJNEN (Eds.), Elsevier, Amsterdam, pp. 270-294. LEVINE, S. (1968) Hormones and conditioning. In Nebraska Symposium on Motivation, W. J. ARNOLD (Ed.), Univ. of Nebraska Press, Lincoln, Neb., pp. 85-101. LEVINE,S. AND JONES,L. E. (1965) Adrenocorticotropic hormone (ACTH) and passive avoidance learning. J. comp. physiol. Psychol., 59, 357-360. LISSAK,K. AND ENDROCZI, E. (1964) Neuroendocrine interrelationships and behavioural processes. In Major Problems in Neuroendocrinology, E. BAJUSZ AND G. JASMIN (Eds.), Karger, Basel, pp. 1-16. LISSAK,K. AND BOHUS,B. (1972) Pituitary hormones and the avoidance behavior of the rat. Znt. J. Psychobiol., 2, 103-1 15. MILLER,N. E. (1969) Learning of visceral and glandular responses. Science, 163, 434-445. MILLER,R. E. AND OGAWA,N. (1962) The effect of adrenocorticotrophic hormone (ACTH) on avoidance conditioning in the adrenalectomized rat. J. comp. physiol. Psychol., 55, 21 1-213. OBRIST,P. A., WEBB,R. A., SUTTERER, J. R. AND HOWARD, J. L. (1970) The cardio-somatic relationship: some reformulations. Psychophysiology, 6, 569-587. RAZRAN, G. (1961) The observable unconscious and the inferable conscious in current Soviet psychophysiology. Psychol. Rev., 68, 81-147. SANDMAN, C. A., KASTIN,A. J. AND SCHALLY, A. V. (1969) Melanocyte-stimulating hormone and learned appetitive behavior. Experientia (Basel), 25, 1001-1002. VANWIMERSMA GREIDANUS, TJ. B. (1970) Effects of steroid on extinction of an avoidance response in rats. A structure-activity relationship study. In Pituitary, Adrenal and the Brain (Progress in Brain Research, Vol. 32), D. DE WIEDAND J. A. W. M. WEIJNEN(Eds.), Elsevier, Amsterdam, pp. 185-191. VANWIMERSMA GREIDANUS, TJ. B. AND DE WIED,D. (1969) Effects of intracerebral implantation of corticosteroids on extinction of an avoidance response in rats, Physiol.. Behav., 4, 365-370. VANWIMERSMA GREIDANUS, TJ. B. AND DE WIED,D. (1971) Effects of systemic and intracerebral administration of two opposite acting ACTH-related peptides on extinction of conditioned avoidance behavior. Neuroendocrinology, 7, 291-301. WEISS,J. M., MCEWEN,B. S., SILVA,M. T. AND KALKUT,M. (1970) Pituitary-adrenal alterations and fear responding. Amer. J. Physiol., 218, 864-868. WEIJNEN,J. A. W. M. AND SLANGEN, J. L. (1970) Effects of ACTH-analogues on extinction of conditioned behavior. In Pituitary, Adrenal and the Brain (Progress in Brain Research, Vol. 321, D. DE WIEDAND J. A. W. M. WEUNEN (Eds.), Elsevier, Amsterdam, pp. 221-233.

420

B. BOHUS

DISCUSSION KITAY:You showed first that cortisone administration accelerated and that ACTH prolonged extinction of conditioned avoidance behavior. Then you showed that ACTH was equally effective in intact and adrenalectomized animals. It seems to me that if the administration of cortisone or of ACTH were to have some physiologic significance, the 14-day adrenalectomized animal would be a super animal with respect to prolonged extinction of behavior and that exogenous ACTH would not have any particular marked effect because endogenous ACTH would have been working in the absence of endogenous corticosterone. Could you explain this?

BOHUS:The experiments you are referring to were performed on rats adrenalectomized just before the first extinction session. Therefore, increase of endogenous ACTH release in the absence of corticosteroids cannot be the primary mechanism for the delayed extinction of the conditioned avoidance response in adrenalectomized, ACTH-treated rats. On the other hand, if adrenalectomy was performed 14 days before the behavioral experiments-in which case the endogenous ACTH release was already increased at the beginning of extinction period-the delay of extinction appeared similar to that of the ACTH-treated rats. This observation favours a physiological role of endogenous ACTH in the extinction behavior. MCEWEN:I wonder if you would comment on the relative effectiveness of various glucocorticoids on behavior. BOHUS:The experiments using passive avoidance situations and comparing the behavioral and ACTH-suppressive potencies of various corticosteroids suggest a “preferential” effect of corticosterone on the behavior of the rat.

KRIVOY: I should like to complement Dr. Bohus on his very fine presentation. Additionally, I should like to point out that in the spinal cord we have not found an action of B-MSH or ACTH1-24 in maximally stimulated spinal cords but only in submaximally stimulated, or pharmacologically depressed cords. This seems to parallel Dr. Bohus’ observations very nicely.