- Email: [email protected]
Effects of ACTH and corticosteroids on animal behavior
Summing up of session I11
Effects of ACTH and corticosteroids on animal behavior I. A. MIRSKY Laboratory of Clinical Sciences, University of Pittsburgh, School of Medicine, 3811 O’Hara Street, Pittsburgh, Penna. 15213 (U.S.A.)
The evaluation of the influence of any endogenous agent on the behavior of animal or man is obfuscated by our ignorance of the nature and processes involved in “behavior”. The procedures employed to investigateactive or passive avoidance behavior, for example, can be specified in detail and thereby defined operationally. The interrelated processes, however, that define “learning”, such as changes in response effectiveness,in motivational state, in the accruing of repetitive experiences with the conditional stimuli, etc., are only indirectly measurable as the behavior o f the animal during a conditioning trial. Accordingly, confusion and controversy is inevitable if different experimental models of ‘‘learning’’ and different “behaviors”, are equated in studies on the influence of any agent. This became evident during the course of the symposium on the “Effects of ACTH and corticosteroids on animal behavior”. It would be quite redundant to review the abundant evidence that endogenous and exogenous adrenocorticotropin (ACTH) and adrenal corticosteroids can influence both the acquisition and retention of an active or psasive avoidance response; ACTH enhances the acquisition and inhibits the extinction of the response while the corticosteroids induce the reverse. These conclusions are supported rather than contradicted by the observations of McEwen and Weiss which suggest that “ACTH and corticosterone have their principle influence under conditions of mild generalized fear”. As Levine, Glassman, McEwen, van Delft, Weijnen and other participants in the symposium emphasized, the effects of these hormones on the conditioned avoidance response need not apply to other types of behavior. Thus, while McEwen reported that high levels of ACTH produced accelerated rates of responding in a discrimination task with food reinforcement while corticosterone reduced this effect, published studies by Levine and Jones, and unpublished studies by Miller and Caul in my laboratory have demonstrated that in contrast to its effect on aversive conditioning, ACTH does not influence other types of appetitive learning in the rat. The contradictions which have arisen occasionally regarding specific experimental results simply emphasize the sensitivity of the experimental subjects to various situational variables which differ from one experiment to another. In accord with the aforementioned are Delacour’s observations that lesions in the centrum medianum parafascicularis complex of the thalamus impair the acquisition
S U M M I N G U P OF SESSION 111
25 1
of some types of behavior and not of others. Thus, he found that the acquisition of two operationally different avoidance behaviors were impaired by the thalamic lesion while the acquisition of two appetitive responses were not affected. In considering that action of any agent, it becomes pertinent to establish the molecular configuration essential to the action. Thus, the extensive studies by De Wied and his colleagues established that a fragment of the molecule of ACTH, viz., the heptapeptide 4-10, is as effective as the intact ACTH molecule in normalizing the impaired acquisition of a shuttle-box avoidance response in hypophysectomized rats and in inhibiting the extinction of avoidance behavior in several active avoidance situations. This led to an exploration of the possibility that other similarly active peptides may be produced in vivo by the adenohypophysis. De Wied, Witter and Lande, starting with a fraction rich in MSH activity, isolated a number of smaller active subfractions. A paucity of material prevented the identification of the amino acid components of these fractions and the determination of whether the active peptides have some common amino acid sequences. Nevertheless, these studies revealed the possibility that a number of small, behaviorally active peptides may be produced by the adenohypophysis. In contrast to the inhibitory action of ACTH - and fragments thereof - on the extinction of an avoidance response, adrenal corticosteroids facilitate the extinction of the same response. Evaluation of a variety of related steroids by Van Wimersma Greidanus led to the conclusion that only the pregnene type steroids, i.e., steroids containing 21 C atoms with a double bond in A or B rings, a keto or hydroxygroup at CSand by preference a keto group at CZO,are capable of facilitating the extinction of a pole-jumping avoidance response. The same structural characteristics might be involved in a number of other effects of steroids on the CNS, viz., anesthesia, facilitation of self-stimulation in some areas and inhibition of such stimulation in other areas, reduction of electroshock thresholds, etc. The comprehensive review by Bohus on the effects of implantations of corticosteroids in the central nervous system demonstrated the involvement of the brain stem and forebrain facilitatory and inhibitory neuronal systems in determining the rate of extinction of an avoidance response. In accord with these observations was the report by McEwen and Weiss on the uptake of labeled corticosterone by various areas of the CNS. These elegant studies revealed a free and rapid exchange of the hormone between the circulating blood and the brain with the hippocampus exhibiting a pronounced tendency to retain the hormone at higher concentrations and for longer intervals than other structures. Cell fractionation studies revealed that hippocampal nuclei have the greatest tendency to bind corticosterone. The effect of such binding on the synthesis of specific enzymes suggested an interaction between the corticosteroids and biogenic amines in the CNS. These fundamental studies promise important insights on the molecular basis of neuronal activity that determine behavior. In similar vein are the studies reported by Glassman, by Gispen and Schotman on the macromolecular changes induced in the brains of animals exposed to a variety of learning experiences. The influence of the pituitary-adrenal axis on the regulation of appetite was the
252
I. A. M I R S K Y
subject of two reports. Denton and Nelson revealed the complexities involved in determining the regulation of the appetite for salt, while Stevenson and Franklin reviewed extensive studies on the regulation of food and water intake. No summary can do justice to the eleven reports which consisted essentially of summaries of a mass of information relevant to various facets of the problem that comprised the subject of the symposium. As was undoubtedly anticipated, the formal presentations and the informal discussions yielded more questions than answers, and more uncertainties than certainties. Yet, the internal consistency of the data from different experimental approaches, in different laboratories in many countries encourages a more intensive pursuit of the mechanisms whereby neuro-endocrine interactions modulate normal and abnormal behaviors. This symposium revealed that the application of the concepts and tools of various disciplines can be focused to identify sites and modes of action of physiological and pharmacological agents within the central nervous system where the intricate interplay of facilitation and inhibition, of arousal and depression, mediate the motivational processes of fear and anxiety.
N O T E OF T H E E D I T O R S
At the conference Drs. DENTON and STEVENSONpresented their papers in session 111; in this book their contributions have been included in the second session.
Effects of ACTH and corticosteroids on animal behavior I. A. MIRSKY Laboratory of Clinical Sciences, University of Pittsburgh, School of Medicine, 3811 O’Hara Street, Pittsburgh, Penna. 15213 (U.S.A.)
The evaluation of the influence of any endogenous agent on the behavior of animal or man is obfuscated by our ignorance of the nature and processes involved in “behavior”. The procedures employed to investigateactive or passive avoidance behavior, for example, can be specified in detail and thereby defined operationally. The interrelated processes, however, that define “learning”, such as changes in response effectiveness,in motivational state, in the accruing of repetitive experiences with the conditional stimuli, etc., are only indirectly measurable as the behavior o f the animal during a conditioning trial. Accordingly, confusion and controversy is inevitable if different experimental models of ‘‘learning’’ and different “behaviors”, are equated in studies on the influence of any agent. This became evident during the course of the symposium on the “Effects of ACTH and corticosteroids on animal behavior”. It would be quite redundant to review the abundant evidence that endogenous and exogenous adrenocorticotropin (ACTH) and adrenal corticosteroids can influence both the acquisition and retention of an active or psasive avoidance response; ACTH enhances the acquisition and inhibits the extinction of the response while the corticosteroids induce the reverse. These conclusions are supported rather than contradicted by the observations of McEwen and Weiss which suggest that “ACTH and corticosterone have their principle influence under conditions of mild generalized fear”. As Levine, Glassman, McEwen, van Delft, Weijnen and other participants in the symposium emphasized, the effects of these hormones on the conditioned avoidance response need not apply to other types of behavior. Thus, while McEwen reported that high levels of ACTH produced accelerated rates of responding in a discrimination task with food reinforcement while corticosterone reduced this effect, published studies by Levine and Jones, and unpublished studies by Miller and Caul in my laboratory have demonstrated that in contrast to its effect on aversive conditioning, ACTH does not influence other types of appetitive learning in the rat. The contradictions which have arisen occasionally regarding specific experimental results simply emphasize the sensitivity of the experimental subjects to various situational variables which differ from one experiment to another. In accord with the aforementioned are Delacour’s observations that lesions in the centrum medianum parafascicularis complex of the thalamus impair the acquisition
S U M M I N G U P OF SESSION 111
25 1
of some types of behavior and not of others. Thus, he found that the acquisition of two operationally different avoidance behaviors were impaired by the thalamic lesion while the acquisition of two appetitive responses were not affected. In considering that action of any agent, it becomes pertinent to establish the molecular configuration essential to the action. Thus, the extensive studies by De Wied and his colleagues established that a fragment of the molecule of ACTH, viz., the heptapeptide 4-10, is as effective as the intact ACTH molecule in normalizing the impaired acquisition of a shuttle-box avoidance response in hypophysectomized rats and in inhibiting the extinction of avoidance behavior in several active avoidance situations. This led to an exploration of the possibility that other similarly active peptides may be produced in vivo by the adenohypophysis. De Wied, Witter and Lande, starting with a fraction rich in MSH activity, isolated a number of smaller active subfractions. A paucity of material prevented the identification of the amino acid components of these fractions and the determination of whether the active peptides have some common amino acid sequences. Nevertheless, these studies revealed the possibility that a number of small, behaviorally active peptides may be produced by the adenohypophysis. In contrast to the inhibitory action of ACTH - and fragments thereof - on the extinction of an avoidance response, adrenal corticosteroids facilitate the extinction of the same response. Evaluation of a variety of related steroids by Van Wimersma Greidanus led to the conclusion that only the pregnene type steroids, i.e., steroids containing 21 C atoms with a double bond in A or B rings, a keto or hydroxygroup at CSand by preference a keto group at CZO,are capable of facilitating the extinction of a pole-jumping avoidance response. The same structural characteristics might be involved in a number of other effects of steroids on the CNS, viz., anesthesia, facilitation of self-stimulation in some areas and inhibition of such stimulation in other areas, reduction of electroshock thresholds, etc. The comprehensive review by Bohus on the effects of implantations of corticosteroids in the central nervous system demonstrated the involvement of the brain stem and forebrain facilitatory and inhibitory neuronal systems in determining the rate of extinction of an avoidance response. In accord with these observations was the report by McEwen and Weiss on the uptake of labeled corticosterone by various areas of the CNS. These elegant studies revealed a free and rapid exchange of the hormone between the circulating blood and the brain with the hippocampus exhibiting a pronounced tendency to retain the hormone at higher concentrations and for longer intervals than other structures. Cell fractionation studies revealed that hippocampal nuclei have the greatest tendency to bind corticosterone. The effect of such binding on the synthesis of specific enzymes suggested an interaction between the corticosteroids and biogenic amines in the CNS. These fundamental studies promise important insights on the molecular basis of neuronal activity that determine behavior. In similar vein are the studies reported by Glassman, by Gispen and Schotman on the macromolecular changes induced in the brains of animals exposed to a variety of learning experiences. The influence of the pituitary-adrenal axis on the regulation of appetite was the
252
I. A. M I R S K Y
subject of two reports. Denton and Nelson revealed the complexities involved in determining the regulation of the appetite for salt, while Stevenson and Franklin reviewed extensive studies on the regulation of food and water intake. No summary can do justice to the eleven reports which consisted essentially of summaries of a mass of information relevant to various facets of the problem that comprised the subject of the symposium. As was undoubtedly anticipated, the formal presentations and the informal discussions yielded more questions than answers, and more uncertainties than certainties. Yet, the internal consistency of the data from different experimental approaches, in different laboratories in many countries encourages a more intensive pursuit of the mechanisms whereby neuro-endocrine interactions modulate normal and abnormal behaviors. This symposium revealed that the application of the concepts and tools of various disciplines can be focused to identify sites and modes of action of physiological and pharmacological agents within the central nervous system where the intricate interplay of facilitation and inhibition, of arousal and depression, mediate the motivational processes of fear and anxiety.
N O T E OF T H E E D I T O R S
At the conference Drs. DENTON and STEVENSONpresented their papers in session 111; in this book their contributions have been included in the second session.