Neal E. Miller

Effects of chronic exposure to stressors on avoidance-escape behavior and on brain norepinephrine.

&NA; A single exposure to a severe stressor (either cold swim or inescapable shock) impairs subsequent performance in a shuttle avoidance‐escape task (1), a deficit attributed to reduction in brain noradrenergic activity produced by these stressors. In the present paper, two experiments are described which examine how repeated exposure to such stressors affects (a) shuttle avoidance‐escape performance (Experiment 1), and (b) aspects of brain norepinephrine metabolism (Experiment 2). Experiment 1 showed that, whereas subjects receiving the single exposure to cold swim or shock showed a large avoidance‐escape deficit, subjects that received repeated exposure to these stressors for 14 days performed similarly to the control group that received no stressor. Experiment 2 showed that, whereas subjects that received one session of the inescapable shock stressor showed a lower level of norepinephrine in hypothalamus and cortex than did subjects that received no shock, subjects that received repeated exposure to inescapable shock or cold swim showed neurochemical “habituation.” Subjects that received repeated shock showed elevated tyrosine hydroxylase activity and no depletion of norepinephrine level, and both repeated shock and cold swim caused a decrease in uptake of 3H‐norepinephrine by slices of cortex in vitro. Thus, it is concluded that the behavioral and neurochemical changes that were observed after the stressful conditions studied are consistent with the hypothesis that changes in avoidance‐escape responding following exposure to these stressful events are due to changes in brain noradrenergic activity.

Chemical Coding of Behavior in the Brain: Stimulating the same place in the brain with different chemicals can elicit different types of behavior

Distinctive patterns of behavior can be elicited by directly stimulating the brain with substances that are normally found in it, or with synthetic compounds resembling these substances. Recent research shows that the response elicited depends on both the site stimulated and the type of chemical used. Compounds of different classes, applied via the same cannula to exactly the same site in the brain, can elicit different kinds of behavior, or opposite effects on the same kind of behavior. This differential sensitivity is useful in tracing the circuits in the brain that control different types of behavior, especially since some of these circuits are intimately interlaced in certain places. A better understanding of the chemical coding of behavioral systems in the brain may also help ultimately to provide a more rational foundation for the discovery of new drugs to treat certain forms of mental disorder.

EFFECTS OF DRUGS ON MOTIVATION: THE VALUE OF USING A VARIETY OF MEASURES

In studying the effects of drugs on motivation it is desirable to use a number of techniques that are as diverse as possible in order to avoid misleading generalizations from effects that are specific to the particular indicator used. Some of the preceding papers by students of Fred Skinner have shown unusual ingenuity in using the same instrumental response (pressing a lever or pecking a t a panel) in a variety of different testing situations. There are definite advantages to this procedure of using the same response in a variety of different tests, and the tests that have been described in the other papers have many additional excellent attributes. For example, bar pressing reinforced on a variable-interval schedule may be maintained a t a constant rate for a considerable time with relatively minor consumption of food (and satiation of drive), so that the course of drug effects may be followed economically throughout fairly long periods. Nevertheless, I believe it is also desirable to have tests that are still more diverse in that they do not depend on the same response and, hence, can insure us against being misled by effects that are specific to that response. In this connection the standardization of naturalistic observation so interestingly presented in the first paper (de Beer and Norton, 1956) should prove fruitful. Since I am advocating the use of a diversity of behavioral measures, i t will be appropriate to illustrate the application of a variety of techniques to a number of different problems. I t will be efficient to begin with a brief reference to the development and use of certain measuring techniques in nonpharmacological studies of “hunger” and “thirst” followed by a description of the application of the same measures to a study of the effects of amphetamine. Next I shall describe some techniques for studying conflict behavior that were used in a theoretical and experimental analysis of some of the social effects of alcohol. I shall also mention an attempt to develop a new behavioral measure of fear-motivated behavior and to use this measure to compare the effects of reserpine on a response motivated by fear with its effects on the same response motivated by hunger. I shall point to the possibility of increasing our knowledge of the central effects of drugs by combining the techniques of using implanted electrodes for electrical stimulation of the brain of the unanesthetized animal with the behavioral techniques for studying avoidance and also reward learning. I shall conclude with the importance of basic research in the development of a science of psychopharmacology (or, if you prefer, behavioral pharmacology) that eventually may provide a rational basis for practical applications to mental hygiene in the same way that organic chemistry provides a basis for the synthesis of new compounds.

Lateral Hypothalamus: Learning of Food-Seeking Response Motivated by Electrical Stimulation

Stimulation of the lateral hypothalamus, which induces eating, resembles hunger in that it motivates rats to learn, for food reward, a response of pressing a bar. The response is discriminatively confined to only a bar that delivers food on either a 100-percent or a partial schedule of reinforceinent. This discriminative responding can be transferred to hunger that is normally induced by deprivation of food.

A Brief Temporal Gradient of Retrograde Amnesia Independent of Situational Change

Rats were given a single electroconvulsive shock at varying intervals after receiving a punishing shock to the feet immediately after stepping into a compartment. Significant amounts of retrograde amnesia for the memory of the punishment was shown when electroconvulsive shock was administered up to and including 30 seconds after the punishment but not at 60 seconds. This brief temporal gradient cannot be explained in ternis of changed stimulus cues or learned interference analogouS to retroactive inhibition.

Monamines as mediators of avoidance-escape behavior.

&NA; A series of three experiments were carried out to test the hypothesis (“motor activation deficit” hypothesis) that the avoidance‐escape deficits observed following certain highly stressful conditions result from changes in activity of noradrenergic (or other monominergic) neural systems. These studies indicate that: (1) Depletion of monamines by a single injection of tetrabenazine produces an active avoidance‐escape deficit when the avoidance‐escape response involves a relatively high degree of motor activity but not when a minimum of motor activity is required. This parallels results found when animals are acutely exposed to a stressor prior to avoidance‐escape testing. (2) Daily injections of tetrabenazine for a period of two weeks, like daily exposure to inescapable shock for the same period of time, markedly attenuates the magnitude of the avoidance‐escape deficit produced by either a single injection of tetrabenazine or single session of inescapable shock. (3) Decreasing the stress‐induced depletion of monamines by the use of an MAO inhibitor serves to protect the animals from the effects of inescapable shock, markedly reducing the avoidance‐escape deficit produced by such shock. It is concluded that these results are consistent with the motor activation deficit hypothesis.

Instrumental Learning of Vasomotor Responses by Rats: Learning to Respond Differentially in the Two Ears

Curarized and artificially respirated rats were rewarded by electrical stimulation of the brain for changes in the balance of vasomotor activity between the two ears. They learned vasomotor responses in one ear that were independent of those in the other ear, in either forepaw, or in the tail, or of changes in heart rate or temperature. In addition to implications for learning theory and psychosomatic medicine, these results indicate a greater specificity of action in the sympathetic nervous system than is usually attributed to it.

SHORTCOMINGS OF FOOD CONSUMPTION AS A MEASURE OF HUNGER; RESULTS FROM OTHER BEHAVIORAL TECHNIQUES

I have been tremendously impressed by the work so effectively reported a t the Conference on which this monograph is based. It is interesting to note, however, that almost all of the studies referred to have used as their index of hunger a single technique, namely, the amount of food eaten. If one is interested in weight regulation, or the long-range balance between energy input and output, this method is an entirely appropriate measure. If one is interested in the broader problem of hunger as a drive, or in the complete mechanism of hunger and satiation, this measure has a number of limitations. It can profitably be supplemented by certain other behavioral techniques. A little thought shows us that the amount of food eaten does not necessarily measure the maximum intensity of the hunger. For example, a persistent, or recurring, low level of hunger which keeps the subject nibbling would cause a large consumption of food, while an intense but rapidly satiated hunger would produce a smaller consumption. Furthermore, the total consumption probably depends on the balance between two factors: hunger and the motivation to stop eating. The foregoing type of analysis is supported by a study by Miller, Bailey, and Stevenson3 on rats with the hypothalamic lesions which cause obesity. On ad lib. feeding tests, these animals ate much more food than did normal controls. But a series of behavioral tests showed that they worked less hard for food and were more easily deterred from eating it. Therefore, we concluded that, under certain conditions, the hypothalamic animals can react to food deprivation with a less intense hunger, even though they eat more on an ad lib. diet.* I shall briefly illustrate two of the behavioral measures which we have found useful in this and other studies. The one is the rate of bar pressing aperiodically reinforced by food as originally developed by Skinner6 a t Harvard and extensively used in our laboratory a t Yale. First, hungry animals are trained to press a bar which always immediately delivers a small pellet of food into a little dish below. Then the mechanism is set so that pressing the bar will deliver food only at certain unpredictable intervals. The animals continue working much like a gambler who operates a slot machine in the hope of hitting the jackpot. The rate at which they work seems to be a good measure of the strength of hunger. Furthermore, since the animals get only tiny bits of food infrequently, relatively long tests can be made without appreciably satiating hunger. The other measure involves pitting the aversion produced by quinine against appetite. Animals are presented with a series of tiny samples of food, each of

Instrumental learning of systolic blood pressure responses by curarized rats: dissociation of cardiac and vascular changes.

&NA; Rats with skeletal muscles paralyzed by curare to rule out the effect of muscular activity were given artificial respiration and were rewarded by escape and/or avoidance of mild electric shock for either increasing or decreasing their systolic blood pressure. A chronic catheter was implanted within the abdominal aorta for measurement of same. Each trial was signaled by the onset of a light and tone; each experimental rat was yoked to a control rat. The yoked control received exactly the same treatment as the experimental S, except that it could do nothing to avoid being shocked, and was shocked whenever the experimental S was shocked. Over‐all group increases and decreases of 22.3% and 19.2%, respectively, were obtained for the experimental groups, and were significantly different from the changes in the control groups. All experimental Ss without exception changed their blood pressure in the rewarded direction. Analyses of heart rate and temperature did not reveal any significant changes either between experimental groups at the beginning, at the end of training, or within experimental groups during training. Implications for learning theory, psychosomatic pathology, and treatment are discussed.

Motivational effects of drugs: Methods which illustrate some general problems in psychopharmacology

I t is well known t h a t people differ wide ly in the i r a p p a r e n t sensit iv i t y to pa in and fear, in the i r genera l level of energy and ac t iv i ty , in f a t igab i l i ty , the need for sleep, and in o ther aspects of dr ive and emot ion such as mood, appe t i t e , s exua l i ty and aggression. Fu r the rmore , the same person m a y v a r y in these respects a t d i f ferent s tages be tween in fancy and seni l i ty , w i th changes in phys ica l condi t ion and disease, or in st i l l more mys te r ious f luc tua t ions . Cer ta in ly w h a t the person has lea rned f rom his life exper iences p lays an i m p o r t a n t p a r t in such differences (DOLLARD and MILLEIr But it also seems that organic factors, both innate and physiologically acquired, contribute to these differences. In other words, ju.st as hereditary and dietary factors contribute to the physical size which makes an individual a better candidate for learning varsity football, there probably are organic differences in the strength of various motivational and emotional mechanisms which make an individual a better prospect for a mental hospital. In short, the organic substrate and the conditions of social learning interact (MILLER1957a). At a time when it seemed relatively hopeless to do much about the organic factors, research was rightly concentrated on the environmental ones. As the recent great advances in biological techniques offer new hope that some of the organic factors contributing to the foregoing differences can be changed, the balance in research is being res tored. B u t these new biological techniques need to be i n t e g ra t e d with new behav io ra l ones to develop a bas ic science of the no rma l phys io logy and the pha rmaco logy of behavior . This pape r s t a r t s w i th a discussion of cer ta in techniques for the expe r imen t a l s t u d y in an imals of mo t iva t i ons and emot ions ~. I n th is