Life Sciences, Vol . 22, pp . 1115-1122 Printed in the U .S .A .
Pergamon Press
ORIGINS AND FUTURE OF BEHAVIORAL PHARMACOLOGY P . B . Dewa Laboratory of Psychobiology New England Regional Primate Research Center Harvard Medical School SUMMARY Behavioral pharmacology has started in earnest in only the last 25 years . Its development depended on the introduction of methods of continuously monitoring significant patterns of behavioral re sponding, objectively and quantitatively, over long periods of time . Most behavioral effects of drugs are understandable only as phenomena occurring in real time and in relation to other influenceson the behavior . Findings in behavioral pharmacology have led to experiments with major implications for psychology as a whole . Behavioral pharmacology is the study of the effects of drugs on the behavior of fairly intact individuals . One would talk of the behavioral pharmacology of a one-armed monkey, but not of the behavioral pharmacology of a liver or of a brain . Behavioral pharmacology ie taxonomically parallel with cellular pharmacology and molecular pharmacology . Cellular pharmacology deals with drug effects on fairly intact cells and molecular pharmacology deals with drug effects on fairly intact molecules . Biochemical pharmacology belongs to a different system of classification as it is identified only by process, chemical process . For unicellular organisms, behavioral pharmacology and cellular pharmacology are the same . The following comments deal with results mostly on monkeys and should therefore not be judged as cellular pharmacology . Like molecular pharmacology, behavioral pharmacology had a few abortive starts . Ehrlich wanted to start molecular pharmacology but techniques were not available . Pavlov wanted to start behavioral pharmacology but his tech niques were not appropriate and he became so inextricably ensnared in the thickets of hypothetical cortical analyzers that it took his Soviet successors 40 years to hack their way out . David Macht at Johns Hopkins commented in 1920 on the neglect of paychopharmacology (his term) . He saw what he wanted to do . and consulted his colleague in psychology, John B . Watson, known as the father of behavioriam(Macht and Mora, 1920) . Unfortunately Watson gave Macht a maze, thereby dooming Macht's attempt to develop a science to failure, for reasons that will become apparent . Still more unfortunately, the maze remained the usual technique of would-be students of behavioral pharmacology for the next 30 years . As much as 23 years after his original paper, Macht was still using Wataon's circular maze, but in the same paper(Macht, 1943) he described a method he himself had devised . The test consisted of timing rats climbing a rope . The teat was adopted by C . Winter at Merck, Rahway(Winter and Flataker, 1951) and from there by the Rhone-Poulenc group in France where it played a role in the discovery of chlorpromazine(Courvoisier, Fournel, Ducrot, Kolaky and Koetschet, 1953) . In 1937, B . F . Skinner wrote a paper with Heron entitled "Effects of caffeine and benzedrine upon conditioning and extinction"(Skinner and Heron, 1937) which really brought concept and technique together and foreshadowed modern 0300-9653/78/0410-1115$02 .00/0 Copyright Q 1978 Pergamon Press
1116
Behavioral Pharmacology
Vol . 22, No .a 13-15,
1978
behavioral pharmacology . It is interesting that the paper not only pioneered behavioral pharmacology but was also one of the very first experimental pâpera on effects of amphetamine on behavior of any kind . In spite of the clear lead, there was little activity until the early The field is 1950'x, when modern behavioral pharmacology began in earnest . therefore about 25 years old and is no doubt entering a new epoch when it will be classical rather than modern . Two developments determined the sudden efflorescence in the early 1950'x . First was the introduction of new drugs with hitherto unrecognized effects . Drugs affecting behavior had been classified either as stimulants and depressants, each occypying some locus on a continuum from stimulation to depression, or as drugs with selective effects on a particular attribute or analgesic, anti-convulsant, or anti-parneurological disorder, for example: kinsoniam. When antihistamine drugs came into wide clinical use in the 1940's it became clear that they all had behavioral effects. (Why there should be resemblancea between the behavioral effects of antihistamines of different chemical classes remains a mystery .) At least two groups decided the behavioral effects were sufficiently interesting to merit study in their own right; Winter and Flataker (1951) and Courvoisier et al . (1953), and from the phenothiazine group of antihistamine drugs came chlorpromazine . From the beginning it was clear that chlorpromazine did not fit into any existing pharmacological classification and the coining of new names like neuroleptic did not conceal the fact . As the use of chlorpromazine for its behavioral effects increased dramatically in the years following its introduction it presented an undeniable challenge to pharmacologicas to analyze its behavioral effects . The second development launching behavioral pharmacology in the 1950's was the introduction of new techniques, by far the moat important being those commonly called operant techniques . Although the term operant behavior refers to a type of behavioral control identified by Skinner, operant techniques have been commonly characterized by the extensive use of automatic programming and recording devices . The use of such techniques in themselves provided a fresh new approach to behavioral pharmacology which I hope you will permit me to I started pharmacology studying THCa in illustrate by personal recollection . 1945 and found it utterly frustrating . In reasonable doses, the THCe available had only behavioral effects and there were no promising techniques in pharmacology for studying behavioral effects . The Skinner and Heron (1937) paper After a year or so of had not been recognized in the pharmacology literature . fruitless efforts, it became necessary to turn to problems accessible to available techniques so THCe were left in abeyance and studies started on histamine and antihistamines on xmooth muscle of guinea pigs isolated in a bath and on blood pressure in cats and so on . Effects were recorded first on smoked drums, Results came from measurements of ups and downs of a conthen on polygraphs . When I tinuous line recording changes in physiological function in real time . joined Rrayer's department in 1952 he sent me over to Cambridge, MA, to nee B . F . Skinner who introduced me Xo C . B . Ferster who in turn took me into their laboratory . And there they were recording something they called operant behavior.a s ups and downs of a continuous line in real time . I was at home at once and determined to follow the lead of Skinner and Heron fifteen years before and to apply the techniques to behavioral pharmacology . To be able to measure something well and display it nicely does not unTo contribute fortunately guarantee that what is measured will be interesting . to pharmacology techniques must show selective effects of drugs . What Skinner and Ferster were recording was repetitive responding of a subject as a funcspecifically, cumulative recording of a pigeon repeatedly pecktion of time : They had xhown that many ing a key that electrically registered each peak .
Behavioral Pharmacology
Vol . 22, No .e 13-15, 1978
1117
different schedules of reinforcement led to many corresponding different patterns of responding . Would the different patterns be selectively affected by drugs? The very first experiments showed that two different patterns of responding were indeed differently affected by a drug, Fig . 1(Dews, 1955) . They
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m~m PENTOBARHITAL FIG. 1 Dose-effect curves of pentobarbital on responding under two different schedules of reinforcement, 15'FI and FR50 . The 15'FI schedule produced an increasing rate of responding through a 15 min . period, the average being 0 .4 responses/ sec. The FR50 schedule produced a high constant rate of responding, averaging 1.7 responses/sec. Note that at 1 and 2 mg pentobarbital, the rate under 15'FI was greatly reduced although the rate under FR50 was actually increased . The only differences between the two situations was the schedule and its consequent pattern of responding . The studies were conducted on 4 pigeons, the response was a peck of a key, electrically recorded, and all 4 pigeons were studied under both 15'FI and FR50 . (From Dews, 1955, by permission of The Williama 6 Wilkin a Co . . Baltimores Maryland .) showed also that pentobarbital could increase as well as decrease rate of responding, and could do either at the same dose in the same individual depending on the schedule with its appropriate dependent pattern of responding, what will be called the schedule-dependent pattern of responding . As the interest in behavioral pharmacology spread, an increasing number of laboratories became involved, and it was soon abundantly clear that many different drugs had very different effects on different schedule-dependent patterns of responding . Reproducible dose-objective effect curves could be determined for any number of different effects for any number of different drugs . Any technique that could do that and was able to show selectivity of different drugs clearly must be exploited . The subsequent history of behavioral pharmacology has been of findings in behavioral pharmacology leading to reappraisal of psychological interpretations
1118
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Vol. 22, No .a 13-15, 1978
of behavioral phenomena leading to new experimental analyses of behavior which then suggested new experiments in behavioral pharmacology and so on in a mutually enhancing cycle or s rather, upward spiral of increasing knowledge . The process is compellingly similar to that between physiological pharmacology and physiology . Consider how knowledge of the autonomic nérvous system developed . Investigations with drugs such as nicotine suggested physiological functions of the autonomic nerwus system, calling for physiological experiments . As the functions were better understood, new pharmacological studies were called for, the level of understanding rising with each upward turn of the spiral . It is this feature of behavioral pharmacology, its mutual heuristic stimulation of experimental analysis of behavior, more than any other, that gives assurance of the correctness of the general approach . One example of a series of mutually enhancing interchanges between behavioral pharmacology and experimental psychology will serve to illustrate the process . The differential sensitivity of different patterns of schedule-de what characteriet~.cs pendent responding of drug effects prompts the question : of the pattern determine the effects of the drug? The most obvious characSome experiments with methamphetateristic is simply the rate of responding . mine and a review of the (very limited) literature on amphetamines showed that whenever the effects could be related to a control rate of responding, the Specifically, all effects were entirely determined by that rate(Dews, 1958) . rates above about 1 response/sec . were decreased and rates below about 1 reaponae/sec . were increased ; and it has since been shown that the higher the rate, the more the proportionate decrease and the lower the rate the more the The relation between log control rate and log proporproportionate increase . tionate effect shows a sensibly linear trend, Fig . 2(Dews and Wenger, 1977) .
AMPHETAMINE-RATS
1 .9 - SSSpMnlq
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1
1
iA -0.S -IS L0ß OF CONTROL itATE~
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FIG. 2 Th e relation between control rate and the effect of amphetamines, summarizing The control rate from the publication results from about 50 published papers . was converted to log base 10 . The effect was defined as rate after drug di Results from the range of vided by control rate and was also converted to log . doses from 1 .8 to 5 .59 um/kg were pooled and so were results on methamphetaThe period of mine, d-amphetamine and (with dosage adjustment) dl-amphetamine .
Vol . 22, No .s 13-15,
1978
Behavioral Pharmacology
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recording was perforce that given in the paper . The line shows linear regreasion weighted by the amount of information summarized by each point. Open circles are for experiments on subjects operating electrical key under a scheClosed circles are for all other experiments, for example, frequency of dule . breaking of a light beam on to a photocell or frequency of grooming . Despite the great scatter, inevitable when measures, doses, drugs and times are pooled, there is a clear downward trend of the points from left to right. The divergent low point at (-0.9, -0 .7) is from the experiments of Geller and Seifter (1960) on suppressed responding and is typical of the effects of amphetamine on suppressed responding . (From Dews and Wehger, 1977, by permission of Academic Press, Inc ., New York, New York .) The rate of responding seemed to determine the effect of amphetamine over the range of available data, without regard to how or what was maintaining that rate, for example, whether the experiments involved food or electric shock to maintain responding . That the effects of a drug are affected by the schedule-dependent responding raises the possibility that the effects of other influences may be also greatly affected by the nature of the schedule-dependent responding on which they are superimposed . For example, responding can be greatly affected by If every response is delivering electric shocks in relation to responses . followed by an electric shock, the rate of responding is typically greatly reduced . Will the effect of an electric shock delivered in relation to a response be affected by the schedule-dependent respo~ing on which it is superimpoaed7 Following a lead of Relleher, Riddle and Cook (1963) who showed surprising persistence of responding when the only maintaining event was occasional delivery of electric shock, Kelleher and Morse (1969) were able to show that delivering an electric shock at a response during appropriate ~chedule-dependent responding could result in the electric shock itself acquiring the ability They showed that squirrel monkeys would go to enhance and maintain responding . on pressing a lever when the only consequence of pressing was occasional deli very of a severe electric shock (many ma) to the tail . The shock was delivered only when the monkey pressed the lever . Reducing or eliminating the shock reduced or abolished responding and responding was reinstated when shock was reintroduced . One monkey continued responding for 170 sessions over a period approaching a year, making an average of over 4,000 responses per session or a total of some 700,000 responses, maintained only by 1,900 ahocka of 12 .6 ma that would not have been delivered if the subject had not pressed the lever . Complementary experiments have shown that pigeons will continûe to respond when the consequence i8 a decrease in the frequency of presentation of food (Smith and Clark, 1972) . The general results are replicable by competent workers and have been confirmed in other laboratories . Thus, food and electric shock can, in certain limited circumstances, function interchangeably as reinforcers, confirming that the distinction between positive and negative rein forcera cannot be made biologically . It need hardly be emphasized the contention is not that food and electric shock are generally interchangeable as behavior modifiers . Under many schedules of presentations and circumstances the two have profoundly different effects, not to speak of the difficulty of maintaining body-weight on a diet only of ahocka . The contention is that the behavioral equivalence of food and shock in any circumstances has great implications for psychological theory . In the usual manner of science, the report of the relation between the control rate of responding and the effects of amphetamine prompted a search for exceptions . Indeed, as early as the early 1960'e clear exception was demonstrated . When a rate of responding was made very low by following each shock with an electric shock, that low rate is not increased by amphetamine and may even be further decreased(Geller and Se after, 1960) . The behavioral
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studies of electric shocks just described lead to investigations to determine whether the effects, or lack of effects, of amphetamine on suppressed responding are specifically related to electric shock . Is responding suppressed by non-noxious stimuli similarly unsusceptible to increase by amphetamine? Are there circumstances where responding suppressed by electric shock may be increased by amphetamine? The answer to both questions is : yes . Responding in rhesus monkeys has been suppressed by a stimulus whose only denotation is that the time when food may be delivered is approaching . Responding was suppressed even so and the suppressed responding was not increased by amphetamine(Dews, 1976) . McKearney and Barrett (1975) have studied squirrel monkeys under long sessions in which 10 minute periods of working toward food alternated with 10 minute periods in which responses postponed for 20 sec . electric shocks that would otherwise have occurred every 5 sec . When every 30th response made as the subject worked towards food was followed by electric shock, responding was greatly suppressed . The suppressed responding, however, was increased many fold by amphetamine, even though the suppression was by electric shock . That the context of a period of responding, in relation to responding and schedules over long periods of time, has latent effects on the control of the responding, again has psychological implications that will lead to new lines of experimentation that, in turn, are likely to lead to new lines in behavioral pharmacology . The series of interchanges between behavioral pharmacology and psychology just outlined is only one of several Lines that have been developing in the last two decades . Everywhere old ideas about what drugs do to behavior are being tested and usually found wanting . Pentobarbital can no longer be described simply as a depressant nor amphetamine as a stimulant . Morphine given to a monkey working alternately toward food and toward an electric shock shows an increase in rate of responding toward the shock but only a decrease in rate of responding toward food(McKearney, 1974) . How can such findings be reconciled with the simple description of morphine as an analgesic? Anew frame of reference for behavioral pharmacology is coming into being and should attract consensus and acceptance in the near future . It should be obvious naw why behavioral pharmacology has developed so late as a field of pharmacology . Drug effects at any point in time may be profoundly affected by what has been going on over long previous periods . Most of the drug effects described make sense only when viewed over substantial periods of time, as is possible only with long-term continuous monitoring . Runway and maze methods of studying behavior, which provide samples only a few seconds in length do not clarify the long term sequential relations . As cardiovascular pharmacology had to wait for Ludwig's kymograph, so behavioral pharmacology had to wait for Skinner's cumulative recorder . What of the future? I expect the present spiral of increasing understanding to continue in the forseeable future without technical constraints and with no dimunition in yield of unexpected and exciting new findings . Illumination of traditional concerns of drug effects on emotions, learning and motivations will not come, but rather other concerns rising out of laboratory findings will replace the traditional concerns almost entirely . Nothing has been said about either neurophysiological or neurochemical mechanisms . We are constantly criticised for this retinence . It is not from a lack of desire to understand mechanisms and we do our beat to follow deve lopments in neurobiology . Most speculations on the neurobiological mechanisms of the sorts of performance we have been describing are, however, so tenuous as to be surely nonsense and I prefer silence to talking nonsense . Perhaps it is a matter of taste, but if it is a matter of taste to prefer Borlag to Lysenko, so be it .
Vol . 22, No .s 13-15, 1978
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ACKNOWLEDGEMENT Portions of this work supported by USPHS Grants MH02094, MH07658, DA004999, RR-00168, and a grant from Hoffmann-La Roche Inc . Dedicated to Otto Rrayer whose encouragement and support made possible many of the beginnings of behavioral pharmacology . I am indebted to my colleagues W .H . Morse and R .T . Kelleher for their invaluable help in preparation of this paper and in the laboratory these many years . REFERENCES
2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 .
S . COURVOISIER, J . FOURNEL, R . DUCROT, M . KOLSKY, AND P . ROETSCHET, Archs . Int . Pharmacodyn . Ther . 9 2 305-361 (1953) . P . B . DEWS, J . Pharmacol.Exp . Therap ., _113 393-401 (1955) . P . B . DEWS, J . Pharmacol . Exp . Therap ., _122 137-147 (1958) . P . B . DEWS, Brit . J . Pharmacol ., _58 451P (1977) . P . B . DEWS and G . R . WENGER, Advances in Behavioral Pharmacology , pp . 167227, Academic Press, New York (1977) I . GELLER and J . SEIFTER, Psychopharmacologia, _1 482-492 (1960) . R . T . KELLEHER, W . C . RIDDLE, and L . COOK, J . Exp . Anal . of Behav ., _6 507517 (1963) . R . T . KELLEliER and W . H . MORSE, J . Exp . Anal . of Behav . _11 819-838 (1968) D . I . MACHT, Exp . Med . of Surg ., _1 260-272 (1943) . D . I . MACHT and C . F . MOKA, J . Pharmaco . Exp . Therap ., _16 219-235 (192021) . J . W . McKEARNEY and J . E . BARRETT, Psychopharmacologia, _41 23-26 (1975) . J . W . MrKFARNFV ~ The J, of Pharmacol . and Exp . Therap ., _190 141-158 (1974) . B . F . SKINNER and W . T . HERON, The Psycholog, Rec ., 1 340-346 (1937) . J . B . SMITH and F . C . CLARK, J . Exp . Anal . of Behav ., _18 1-12 (1972) . C . A . WINTER and L . FLATARER, J . Pharmacol ., 101 156-162 (1951) .
Pergamon Press
ORIGINS AND FUTURE OF BEHAVIORAL PHARMACOLOGY P . B . Dewa Laboratory of Psychobiology New England Regional Primate Research Center Harvard Medical School SUMMARY Behavioral pharmacology has started in earnest in only the last 25 years . Its development depended on the introduction of methods of continuously monitoring significant patterns of behavioral re sponding, objectively and quantitatively, over long periods of time . Most behavioral effects of drugs are understandable only as phenomena occurring in real time and in relation to other influenceson the behavior . Findings in behavioral pharmacology have led to experiments with major implications for psychology as a whole . Behavioral pharmacology is the study of the effects of drugs on the behavior of fairly intact individuals . One would talk of the behavioral pharmacology of a one-armed monkey, but not of the behavioral pharmacology of a liver or of a brain . Behavioral pharmacology ie taxonomically parallel with cellular pharmacology and molecular pharmacology . Cellular pharmacology deals with drug effects on fairly intact cells and molecular pharmacology deals with drug effects on fairly intact molecules . Biochemical pharmacology belongs to a different system of classification as it is identified only by process, chemical process . For unicellular organisms, behavioral pharmacology and cellular pharmacology are the same . The following comments deal with results mostly on monkeys and should therefore not be judged as cellular pharmacology . Like molecular pharmacology, behavioral pharmacology had a few abortive starts . Ehrlich wanted to start molecular pharmacology but techniques were not available . Pavlov wanted to start behavioral pharmacology but his tech niques were not appropriate and he became so inextricably ensnared in the thickets of hypothetical cortical analyzers that it took his Soviet successors 40 years to hack their way out . David Macht at Johns Hopkins commented in 1920 on the neglect of paychopharmacology (his term) . He saw what he wanted to do . and consulted his colleague in psychology, John B . Watson, known as the father of behavioriam(Macht and Mora, 1920) . Unfortunately Watson gave Macht a maze, thereby dooming Macht's attempt to develop a science to failure, for reasons that will become apparent . Still more unfortunately, the maze remained the usual technique of would-be students of behavioral pharmacology for the next 30 years . As much as 23 years after his original paper, Macht was still using Wataon's circular maze, but in the same paper(Macht, 1943) he described a method he himself had devised . The test consisted of timing rats climbing a rope . The teat was adopted by C . Winter at Merck, Rahway(Winter and Flataker, 1951) and from there by the Rhone-Poulenc group in France where it played a role in the discovery of chlorpromazine(Courvoisier, Fournel, Ducrot, Kolaky and Koetschet, 1953) . In 1937, B . F . Skinner wrote a paper with Heron entitled "Effects of caffeine and benzedrine upon conditioning and extinction"(Skinner and Heron, 1937) which really brought concept and technique together and foreshadowed modern 0300-9653/78/0410-1115$02 .00/0 Copyright Q 1978 Pergamon Press
1116
Behavioral Pharmacology
Vol . 22, No .a 13-15,
1978
behavioral pharmacology . It is interesting that the paper not only pioneered behavioral pharmacology but was also one of the very first experimental pâpera on effects of amphetamine on behavior of any kind . In spite of the clear lead, there was little activity until the early The field is 1950'x, when modern behavioral pharmacology began in earnest . therefore about 25 years old and is no doubt entering a new epoch when it will be classical rather than modern . Two developments determined the sudden efflorescence in the early 1950'x . First was the introduction of new drugs with hitherto unrecognized effects . Drugs affecting behavior had been classified either as stimulants and depressants, each occypying some locus on a continuum from stimulation to depression, or as drugs with selective effects on a particular attribute or analgesic, anti-convulsant, or anti-parneurological disorder, for example: kinsoniam. When antihistamine drugs came into wide clinical use in the 1940's it became clear that they all had behavioral effects. (Why there should be resemblancea between the behavioral effects of antihistamines of different chemical classes remains a mystery .) At least two groups decided the behavioral effects were sufficiently interesting to merit study in their own right; Winter and Flataker (1951) and Courvoisier et al . (1953), and from the phenothiazine group of antihistamine drugs came chlorpromazine . From the beginning it was clear that chlorpromazine did not fit into any existing pharmacological classification and the coining of new names like neuroleptic did not conceal the fact . As the use of chlorpromazine for its behavioral effects increased dramatically in the years following its introduction it presented an undeniable challenge to pharmacologicas to analyze its behavioral effects . The second development launching behavioral pharmacology in the 1950's was the introduction of new techniques, by far the moat important being those commonly called operant techniques . Although the term operant behavior refers to a type of behavioral control identified by Skinner, operant techniques have been commonly characterized by the extensive use of automatic programming and recording devices . The use of such techniques in themselves provided a fresh new approach to behavioral pharmacology which I hope you will permit me to I started pharmacology studying THCa in illustrate by personal recollection . 1945 and found it utterly frustrating . In reasonable doses, the THCe available had only behavioral effects and there were no promising techniques in pharmacology for studying behavioral effects . The Skinner and Heron (1937) paper After a year or so of had not been recognized in the pharmacology literature . fruitless efforts, it became necessary to turn to problems accessible to available techniques so THCe were left in abeyance and studies started on histamine and antihistamines on xmooth muscle of guinea pigs isolated in a bath and on blood pressure in cats and so on . Effects were recorded first on smoked drums, Results came from measurements of ups and downs of a conthen on polygraphs . When I tinuous line recording changes in physiological function in real time . joined Rrayer's department in 1952 he sent me over to Cambridge, MA, to nee B . F . Skinner who introduced me Xo C . B . Ferster who in turn took me into their laboratory . And there they were recording something they called operant behavior.a s ups and downs of a continuous line in real time . I was at home at once and determined to follow the lead of Skinner and Heron fifteen years before and to apply the techniques to behavioral pharmacology . To be able to measure something well and display it nicely does not unTo contribute fortunately guarantee that what is measured will be interesting . to pharmacology techniques must show selective effects of drugs . What Skinner and Ferster were recording was repetitive responding of a subject as a funcspecifically, cumulative recording of a pigeon repeatedly pecktion of time : They had xhown that many ing a key that electrically registered each peak .
Behavioral Pharmacology
Vol . 22, No .e 13-15, 1978
1117
different schedules of reinforcement led to many corresponding different patterns of responding . Would the different patterns be selectively affected by drugs? The very first experiments showed that two different patterns of responding were indeed differently affected by a drug, Fig . 1(Dews, 1955) . They
0 P
W F
sAL
.Y6
.6
1
~
4
6.E
m~m PENTOBARHITAL FIG. 1 Dose-effect curves of pentobarbital on responding under two different schedules of reinforcement, 15'FI and FR50 . The 15'FI schedule produced an increasing rate of responding through a 15 min . period, the average being 0 .4 responses/ sec. The FR50 schedule produced a high constant rate of responding, averaging 1.7 responses/sec. Note that at 1 and 2 mg pentobarbital, the rate under 15'FI was greatly reduced although the rate under FR50 was actually increased . The only differences between the two situations was the schedule and its consequent pattern of responding . The studies were conducted on 4 pigeons, the response was a peck of a key, electrically recorded, and all 4 pigeons were studied under both 15'FI and FR50 . (From Dews, 1955, by permission of The Williama 6 Wilkin a Co . . Baltimores Maryland .) showed also that pentobarbital could increase as well as decrease rate of responding, and could do either at the same dose in the same individual depending on the schedule with its appropriate dependent pattern of responding, what will be called the schedule-dependent pattern of responding . As the interest in behavioral pharmacology spread, an increasing number of laboratories became involved, and it was soon abundantly clear that many different drugs had very different effects on different schedule-dependent patterns of responding . Reproducible dose-objective effect curves could be determined for any number of different effects for any number of different drugs . Any technique that could do that and was able to show selectivity of different drugs clearly must be exploited . The subsequent history of behavioral pharmacology has been of findings in behavioral pharmacology leading to reappraisal of psychological interpretations
1118
Behavioral Pharmacology
Vol. 22, No .a 13-15, 1978
of behavioral phenomena leading to new experimental analyses of behavior which then suggested new experiments in behavioral pharmacology and so on in a mutually enhancing cycle or s rather, upward spiral of increasing knowledge . The process is compellingly similar to that between physiological pharmacology and physiology . Consider how knowledge of the autonomic nérvous system developed . Investigations with drugs such as nicotine suggested physiological functions of the autonomic nerwus system, calling for physiological experiments . As the functions were better understood, new pharmacological studies were called for, the level of understanding rising with each upward turn of the spiral . It is this feature of behavioral pharmacology, its mutual heuristic stimulation of experimental analysis of behavior, more than any other, that gives assurance of the correctness of the general approach . One example of a series of mutually enhancing interchanges between behavioral pharmacology and experimental psychology will serve to illustrate the process . The differential sensitivity of different patterns of schedule-de what characteriet~.cs pendent responding of drug effects prompts the question : of the pattern determine the effects of the drug? The most obvious characSome experiments with methamphetateristic is simply the rate of responding . mine and a review of the (very limited) literature on amphetamines showed that whenever the effects could be related to a control rate of responding, the Specifically, all effects were entirely determined by that rate(Dews, 1958) . rates above about 1 response/sec . were decreased and rates below about 1 reaponae/sec . were increased ; and it has since been shown that the higher the rate, the more the proportionate decrease and the lower the rate the more the The relation between log control rate and log proporproportionate increase . tionate effect shows a sensibly linear trend, Fig . 2(Dews and Wenger, 1977) .
AMPHETAMINE-RATS
1 .9 - SSSpMnlq
rIAF-
8
0
-1-0
I
D
1
O
1
1
iA -0.S -IS L0ß OF CONTROL itATE~
I
0
I
*OS
FIG. 2 Th e relation between control rate and the effect of amphetamines, summarizing The control rate from the publication results from about 50 published papers . was converted to log base 10 . The effect was defined as rate after drug di Results from the range of vided by control rate and was also converted to log . doses from 1 .8 to 5 .59 um/kg were pooled and so were results on methamphetaThe period of mine, d-amphetamine and (with dosage adjustment) dl-amphetamine .
Vol . 22, No .s 13-15,
1978
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recording was perforce that given in the paper . The line shows linear regreasion weighted by the amount of information summarized by each point. Open circles are for experiments on subjects operating electrical key under a scheClosed circles are for all other experiments, for example, frequency of dule . breaking of a light beam on to a photocell or frequency of grooming . Despite the great scatter, inevitable when measures, doses, drugs and times are pooled, there is a clear downward trend of the points from left to right. The divergent low point at (-0.9, -0 .7) is from the experiments of Geller and Seifter (1960) on suppressed responding and is typical of the effects of amphetamine on suppressed responding . (From Dews and Wehger, 1977, by permission of Academic Press, Inc ., New York, New York .) The rate of responding seemed to determine the effect of amphetamine over the range of available data, without regard to how or what was maintaining that rate, for example, whether the experiments involved food or electric shock to maintain responding . That the effects of a drug are affected by the schedule-dependent responding raises the possibility that the effects of other influences may be also greatly affected by the nature of the schedule-dependent responding on which they are superimposed . For example, responding can be greatly affected by If every response is delivering electric shocks in relation to responses . followed by an electric shock, the rate of responding is typically greatly reduced . Will the effect of an electric shock delivered in relation to a response be affected by the schedule-dependent respo~ing on which it is superimpoaed7 Following a lead of Relleher, Riddle and Cook (1963) who showed surprising persistence of responding when the only maintaining event was occasional delivery of electric shock, Kelleher and Morse (1969) were able to show that delivering an electric shock at a response during appropriate ~chedule-dependent responding could result in the electric shock itself acquiring the ability They showed that squirrel monkeys would go to enhance and maintain responding . on pressing a lever when the only consequence of pressing was occasional deli very of a severe electric shock (many ma) to the tail . The shock was delivered only when the monkey pressed the lever . Reducing or eliminating the shock reduced or abolished responding and responding was reinstated when shock was reintroduced . One monkey continued responding for 170 sessions over a period approaching a year, making an average of over 4,000 responses per session or a total of some 700,000 responses, maintained only by 1,900 ahocka of 12 .6 ma that would not have been delivered if the subject had not pressed the lever . Complementary experiments have shown that pigeons will continûe to respond when the consequence i8 a decrease in the frequency of presentation of food (Smith and Clark, 1972) . The general results are replicable by competent workers and have been confirmed in other laboratories . Thus, food and electric shock can, in certain limited circumstances, function interchangeably as reinforcers, confirming that the distinction between positive and negative rein forcera cannot be made biologically . It need hardly be emphasized the contention is not that food and electric shock are generally interchangeable as behavior modifiers . Under many schedules of presentations and circumstances the two have profoundly different effects, not to speak of the difficulty of maintaining body-weight on a diet only of ahocka . The contention is that the behavioral equivalence of food and shock in any circumstances has great implications for psychological theory . In the usual manner of science, the report of the relation between the control rate of responding and the effects of amphetamine prompted a search for exceptions . Indeed, as early as the early 1960'e clear exception was demonstrated . When a rate of responding was made very low by following each shock with an electric shock, that low rate is not increased by amphetamine and may even be further decreased(Geller and Se after, 1960) . The behavioral
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studies of electric shocks just described lead to investigations to determine whether the effects, or lack of effects, of amphetamine on suppressed responding are specifically related to electric shock . Is responding suppressed by non-noxious stimuli similarly unsusceptible to increase by amphetamine? Are there circumstances where responding suppressed by electric shock may be increased by amphetamine? The answer to both questions is : yes . Responding in rhesus monkeys has been suppressed by a stimulus whose only denotation is that the time when food may be delivered is approaching . Responding was suppressed even so and the suppressed responding was not increased by amphetamine(Dews, 1976) . McKearney and Barrett (1975) have studied squirrel monkeys under long sessions in which 10 minute periods of working toward food alternated with 10 minute periods in which responses postponed for 20 sec . electric shocks that would otherwise have occurred every 5 sec . When every 30th response made as the subject worked towards food was followed by electric shock, responding was greatly suppressed . The suppressed responding, however, was increased many fold by amphetamine, even though the suppression was by electric shock . That the context of a period of responding, in relation to responding and schedules over long periods of time, has latent effects on the control of the responding, again has psychological implications that will lead to new lines of experimentation that, in turn, are likely to lead to new lines in behavioral pharmacology . The series of interchanges between behavioral pharmacology and psychology just outlined is only one of several Lines that have been developing in the last two decades . Everywhere old ideas about what drugs do to behavior are being tested and usually found wanting . Pentobarbital can no longer be described simply as a depressant nor amphetamine as a stimulant . Morphine given to a monkey working alternately toward food and toward an electric shock shows an increase in rate of responding toward the shock but only a decrease in rate of responding toward food(McKearney, 1974) . How can such findings be reconciled with the simple description of morphine as an analgesic? Anew frame of reference for behavioral pharmacology is coming into being and should attract consensus and acceptance in the near future . It should be obvious naw why behavioral pharmacology has developed so late as a field of pharmacology . Drug effects at any point in time may be profoundly affected by what has been going on over long previous periods . Most of the drug effects described make sense only when viewed over substantial periods of time, as is possible only with long-term continuous monitoring . Runway and maze methods of studying behavior, which provide samples only a few seconds in length do not clarify the long term sequential relations . As cardiovascular pharmacology had to wait for Ludwig's kymograph, so behavioral pharmacology had to wait for Skinner's cumulative recorder . What of the future? I expect the present spiral of increasing understanding to continue in the forseeable future without technical constraints and with no dimunition in yield of unexpected and exciting new findings . Illumination of traditional concerns of drug effects on emotions, learning and motivations will not come, but rather other concerns rising out of laboratory findings will replace the traditional concerns almost entirely . Nothing has been said about either neurophysiological or neurochemical mechanisms . We are constantly criticised for this retinence . It is not from a lack of desire to understand mechanisms and we do our beat to follow deve lopments in neurobiology . Most speculations on the neurobiological mechanisms of the sorts of performance we have been describing are, however, so tenuous as to be surely nonsense and I prefer silence to talking nonsense . Perhaps it is a matter of taste, but if it is a matter of taste to prefer Borlag to Lysenko, so be it .
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ACKNOWLEDGEMENT Portions of this work supported by USPHS Grants MH02094, MH07658, DA004999, RR-00168, and a grant from Hoffmann-La Roche Inc . Dedicated to Otto Rrayer whose encouragement and support made possible many of the beginnings of behavioral pharmacology . I am indebted to my colleagues W .H . Morse and R .T . Kelleher for their invaluable help in preparation of this paper and in the laboratory these many years . REFERENCES
2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 .
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