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Wednesday, 16.10.2019

In Celebration of Conan Kornetsky

(1926 -2018)

by Thomas A. Ban

 

            By the mid-1990s the pioneering generation in neuropsychopharmacology was fading away. To preserve their legacy the late Oakley Ray (1931-2007), at the time Secretary of the American College of Neuropsychopharmacology (ACNP), generated funds from Solway Pharmaceuticals for the founding of the ACNP-Solway Archives in Neuropsychopharmacology. Ray also arranged for the videotaping of interviews (mainly by their peers) with the pioneers, mostly at annual meetings, to be stored in the archives (Ban 2011a). Conan Kornetsky was interviewed twice, first by George F. Koob at the Annual Meeting of the College held in San Juan, Puerto Rico, on December 12, 1995, then by Thomas A. Ban on December 10, 2002, also at the Annual Meeting of the College, in San Juan  (Blackwell 2011; Kleber 2011a).

            The endeavor that was to become known as the “oral history project” is based on 235 videotaped interviews conducted by 66 interviewers with 213 interviewees which, on the basis of their content, were divided and edited into a 10-volume series created by Thomas A. Ban in collaboration with nine colleagues who were to become volume editors (Ban 2011b). The transcripts of Conan Kornetsky’s interviews were included in Volumes Six (Addiction) and Nine (Update) of the series, edited by Herbert Kleber and Barry Blackwell, respectively (Blackwell 2011; Kleber 2011a).

            The series was published by the ACNP with the title “An Oral History of Neuropsychopharmacology Peer Interviews The First Fifty Years” and released  at the 50th Anniversary Meeting of the College in 2011 (Ban 2011a).

            Conan Kornetsky was born in 1926 in Portland, Ohio. He received his BA in Psychology from the University of Maine in 1948. His undergraduate work was interrupted for almost two years, from March 1944 to November 1955, for service in the US Army Air Corps (Kleber 2011b).

            In the fall of 1948, Kornetsky enrolled at the University of Kentucky for his PhD and at the same time got a job at the Addiction Research Center in Lexington, Kentucky. During his years in Lexington, from 1948 to 1952, he published a series of papers with Harris Hill and Abraham Wikler along with a dissertation that demonstrated the importance of morphine’s effect on anxiety and the contribution of this action to morphine’s analgesic effect (Hill, Flanary, Kornetsky and Wikler 1952; Kleber 2011b).

            In the early 1950s Conan Kornetsky was a member of Harris Isbell’s team in Lexington that reported on experimental findings in chronic barbiturate intoxication (Isbell, Altschul,  Kornetsky et  al. 1950). In a subsequent report Kornetsky provided more details of his findings on the psychological effects of chronic barbiturate use (Kornetsky 1954).

            It was also in the early 1950s that Kornetsky began his research on the effects of anxiety and morphine on the anticipation and perception of painful radiating thermal stimuli (Kornetsky 1954). During this time he also extended the scope of these studies to the pharmacology of nociception. In the early years of the 21st century he reported that using thermal radiation and intra-cerebral electric stimulation, showed no difference in nociceptive threshold and analgesic response to morphine between old and young rats (Ban 2011d; Crosby, Knapp, Kornetsky 2006). He also found, in collaboration with Knapp, Tozier and Pak, that medial forebrain stimulation enhanced intracranial nociception and “attenuated” morphine analgesia (Ban 2011d; Kornetsky, Knapp, Tozier and Pak 2010). 

            After receiving his PhD in Clinical Psychology from the University of Kentucky in June 1952, he took a position at the National Institute of Mental Health (NIMH) and carried out a field study of juvenile addiction in New York City (Kleber 2011b). Subsequently, he was assigned to study the effects of lysergic acid diethylamide (LSD) with Murray Jarvik at Mount Sinai Hospital in New York City.  He spent the next five years, from September 1954 to June 1959, at NIMH in the Laboratory of Clinical Science (Kornetsky 1957).

            In 1954, Kornetsky began a comprehensive series of experiments in collaboration with Allan F. Mirsky on the behavioral effects of centrally acting drugs on human behavior. Findings in these studies led to the postulation that the functional deficit in schizophrenia was due to a centrally over-aroused state that resulted in “compromised filtering” of incoming stimuli (Ban 2011c; Kornetsky 1972).  Using the Continuous Performance Test (CPT) he found that approximately 40% of unmedicated schizophrenic patients showed a deficit in attention. Performance on the CPT correlated negatively with mental illness in the family, whereas treatment with neuroleptic medication improved performance.  Yet, with sensory overload, non-medicated schizophrenic patients, even in “good remission” (holding jobs and functioning socially), showed a deficit on the CPT (Ban 2011c; Kleber 2011b).

            In late 1959 Kornetsky moved from NIMH to the Boston University School of Medicine, Departments of Psychiatry and Pharmacology, where he remained for the rest of his professional life (Kleber 2011 b). During his tenure at Boston University, Kornetsky, in the 1970s, developed a psychophysical method for determining the threshold for rewarding intracranial self-stimulation and, with the employment of his method, was among the first to show that both morphine and alcohol increased sensitivity for rewarding brain stimulation (Bain and Kornetsky 1989; Esposito and Kornetsky 1978; Marcus and Kornetsky 1974). By the judicious use of opiate, dopamine and noradrenergic agonists and antagonists he provided evidence for the involvement dopamine in the development of substance abuse by its rewarding effect on brain stimulation by substances of abuse (Kornetsky and Duvauchelle 1994).  

            With the employment of the 2 [14C] deoxyglucose autoradiographic method, in collaboration with Linda Porrino, Kornetsky found that in addition to the nucleus accumbens, the olfactory tubercle may also play an important role in the reinforcing effects of brain-stimulation (Kornetsky, Houston-Lyons and Porrino 1994).  Furthermore, by using the 2DG technique Kornetsky and associates also found that morphine in the presence of pain does not simply reduce metabolic activity in the brain, but it actually increases metabolic activity in the midbrain, suggesting that morphine’s analgesic action is an active process. 

            In his Dramatis Persona in Volume Six of ACNP’s Oral History series, Herbert Kleber suggests that Conan Kornetsky’s research led to four major and enduring seminal contributions (Kleber 2011b): first, his early work in schizophrenia identified an important, perhaps critically important, attentional deficit (Kornetsky 1972);  second, the innovativeness in his research directions and techniques opened whole new avenues of research;  third, the long-term effects of drugs of abuse characterized by Kornetsky laid the framework for the study of plasticity of the brain associated with modern theories of tolerance and physical dependence; and fourth, his work with drugs and brain stimulation reward clearly demonstrated the role of the reward system in drug dependence (Esposito  and Kornetsky 1978).

            Conan Kornetsky died in Newton, Massachusetts, on December 23, 2018, at age 92.

            Edited versions of George F. Koob’s and Thomas A. Ban’s interviews with Conan Kornetsky are presented below.

George F. Koob’s interview with Conan Kornetsky, conducted  in San Juan, Puerto Rico, December 12, 1995.

GK: Hi, I am George Koob.  I am at the Scripps Research Institute in La Jolla, California, and I am interviewing Conan Kornetsky who is a professor in psychiatry and pharmacology of the Boston University School of Medicine.  Dr. Kornetsky is the former editor of Psychopharmacology, the Journal, and he is also a founding fellow of the ACNP, and he has worked for many years in both animal and clinical aspects of psychopharmacology.  And, so we will begin today with asking Dr. Kornetsky what sort of training did you have to begin in this field and was there any kind of specialized training in this area?  And, also how did you become interested in psychopharmacology?

CK: Well, I think I was interested in science, first, and started my undergraduate work in the College of Engineering at the University of Maine, Oromo. This was interrupted when I went into the Army Air Corp in March 1944 during WW II. When I was discharged from the service in December 1945 and went back to school at the University of Maine and I decided that I did not want to be an engineer and started my second year of college as a Psychology major. As a senior thesis I decided to compare social attitudes of members of Phi Beta Kappa with those of the Tau Beta Pi, the national honorary engineering society. Because I had no hope of being elected to an honorary academic society I decided that I would study the members.  The findings were interesting in that, as expected, on every test of liberalism the Phi Beta Kappa scored higher; however, I could find no difference between the two groups in religious upbringing, occupation of major bread winner in the family or any major social or economic family difference. From this I concluded that the differences I saw were the result of their respective curriculum. Many years later I heard a symposium lecture by a sociology professor that compared engineering and liberal arts students and came to a similar conclusion, that curriculum counts. 

            As a senior I decided I wanted to be a clinical psychologist. The only US approved clinical psychology program in New England at that time was at Yale. Considering the fact that I had a very uneven academic record I did not apply to Yale. A young philosophy professor said he had been at a University in Kentucky before coming to Maine and suggested that I see if the University of Kentucky had an approved program. If so he said he would write the type of letter that would get me accepted and it did. Although I was interested in science my primary ambition was to become a clinical psychologist and work with patients. Although I had the GI Bill when I went to Kentucky I found I needed additional funds, so I found a job as a “House Boy” at a sorority house. However, because as an undergraduate at the University of Maine where I took a course in IQ testing that qualified me as a mental tester, about a month later I was offered a job in the Clinical Psychology Department at the US Public Health Service Hospital/Prison for the incarceration and treatment of drug  addicts in Lexington. Because the stipend was “board, room and laundry” it was obvious that I needed to make a career decision. As you probably suspected I decided to give up the sorority house boy job. The hospital job was quite consuming. I administered every afternoon, four to five days a week two to three IQ tests. In the evenings I started to spend time in the day-rooms of the addict patients. The most interesting day room was the one in the Research Department. Harris Isbell, who was the Director of Research, came around almost every evening to check on patients who were subjects in experiments. About this time he was planning an experiment of chronic barbiturate administration in human volunteers to determine if the convulsions and psychosis that had occasionally been reported were due to withdrawal or was it an intoxication phenomenon. Because Isbell did not have a psychologist in the Research Department and luckily for me he believed that a student who was approximately two months into his graduate program was qualified; I was invited to participate. Thus, my entrance into the field of psychopharmacology was based on a number of chance events with the elimination of any single one may have resulted on a different career choice. This experiment was carried out in five post-addict volunteers and I was one of the co-authors of the paper published on it. It was the first paper in my research bibliography; it was written by Isbell, Altshul, Kornetsky, Eisenman, and Fraser and published in the Archives of Neurology and Psychiatry in 1950. Isbell was pleased enough to suggest that I submit the detailed psychological finding in a separate paper that was published in the Archives of Neurology and Psychiatry, written by me alone in 1951.The surprising thing was that in 1948 and ‘49 when that experiment took place it was not known that there was physical dependence to barbiturates.  In some way that clinical experiment probably had more direct impact upon what clinicians do than anything I have ever worked on. This long wordy answer is how I became interested and committed to a research career.

GK: Now, was this part of your graduate work or something prior to your graduate work?

CK: No, it wasn’t actually part of my graduate work; however, it contributed to my graduate education. It was actually carried out while I was a first year graduate student.  During that time the research was so time consuming that I actually began to have academic difficulty. However, the Chairman of the Psychology Department at the time, James Calvin, in order that I continue my research began giving me academic credit for my work at the hospital allowing me to not take as many courses as most of the graduate students. He did require that I give a seminar on my research at the weekly department seminars every semester and most important pass the PhD qualifying exam that consisted of seven areas of psychology.  In fact, I began to have trouble in graduate school because I found that it was more fun doing the research than to go to class. 

GK: So, what was your dissertation in for graduate school and where, so we have all the details?

CK: Okay, well, my dissertation was at the University of Kentucky, and although my dissertation advisor of record was the Chairman of the Psychology Department, my de facto thesis mentor was actually Abraham Wikler at the Addiction Center where the work was done. My dissertation was on the effects of anxiety and morphine on the perception of pain in humans.  It was part of a whole series of studies done in Lexington, trying to understand the analgesic action of morphine.

GK: Do you want to, maybe, kind of say some things about your interactions with Abraham Wikler, given that he was probably one of the primary movers in the group that you worked with.

CK: Well, at that time, Abe was very interested in trying to understand the role of anxiety in the analgesic effect of morphine and how did this contribute to its addiction liability.  I think I should mention what my first encounter with Abe was like.  The first year I was at the Addiction Center Abe was on sabbatical. In June of that year, 1949, I was on vacation when Abe returned. At my first day back I heard that Abe had returned.  Although he was back for only a month he had already started doing experiments in spinal dog preparations. In these experiments he recorded autonomic responses of the animal on smoked loops of paper which were later fixed by shellacking the loops. Prior to fixing them with shellac he had them hanging on pegs just outside of his door. In my eagerness to meet him I brushed against some of the unshellacked loops. I then heard the first words that Abe ever said, or I should say, yelled at me. It went something like, “Who the hell is this stupid ass?”  After this he became my mentor and great friend. Also, we were interested in what Abe was always interested in, what was the driving force resulting in addiction and why people liked morphine and heroin; you have to remember at that time the major belief was that drugs were reinforcing because they normalized pathology.  And, most of the clinical work at the hospital at that time and a lot of the research was directed to understanding the psychopathology that made individuals vulnerable.  Wikler believed that an important component of opiate action was its anxiolytic effects. Because of this we developed a very simple experimental model for the study of anxiety. Of interest was the directness of Wikler and his willingness to reevaluate his position.  Most mornings at 8:00, Abe, Harris Hill and I would meet in the cafeteria for coffee. Harris Hill was a recent PhD in experimental psychology from Indiana University. Although a new PhD, Harris did not attend graduate school until he was, if I remember correctly, in his late 30s. During these meetings of the three of us which were more mini-seminars Abe would conduct discussions about current research, future research and the field in general, and at one of these mini-seminars, I suggested a method to experimentally study the effects of morphine on anxiety.  It was a simple reaction time experiment in which the subject would release a telegraph key at the onset of either of two lights.  The only difference was that with one light it indicated that the subject would receive an electric shock to his hand at the completion of the response. The criterion of receiving the shock was based on the subject’s medium reaction time on a previous series of unpunished reaction times. If the subject’s reaction time shortened in order to avoid the electric shock, the criterion to escape the shock was increased in the next series and so on. When I first presented this model Abe’s first response was something like, “that is the most stupid idea I have ever heard.” However, a few days later at our morning meeting he said that he has been thinking about the experiment and if we made certain changes he thought it might work.  With Abe’s suggestions the experiment did work.  In a control situation the subject’s reaction at first became faster but as the criterion was raised, the reaction time precipitously became disorganized and markedly slowed.  Morphine normally caused an increase in reaction time and under these conditions the fastest reaction time was when the experiment was carried out under the influence of morphine. Of interest was that we ran a few non-addict volunteers. They were psychiatric residents at the hospital. There were two sessions for each subject, one control and one with morphine. If the first session was a control, if I remember correctly, none of the residents returned for the second sessions. Also, we reactivated an ulcer of one of the non-addict subjects.

GK: Now, after you finished your PhD at the University of Kentucky, did you do a postdoc like people do today?

CK: No, I believe post doc appointments, if any, were rare in 1952. The strange part of the story was that when I was a graduate student I also held a commission in the US Army reserves.  Although I had served in the Army during WWII when I was an undergraduate student and I was under the GI Bill, which was enough for tuition and books, I had to supplement this by working in food service. Also, I found I could pick up additional funds by taking ROTC. So, when I received my BA degree I also received a commission in the US Army, never thinking that we would soon be in another war, the Korean War. Thus, while I was in graduate school and working at the USPHS hospital I was called to active duty in the Army. Because the USPHS, a commission corps, was still part of the armed forces, a hold-over from WWII, Dr. Isbell was able to have me transferred from the Army to the commission corps of the USPHS while I was still a graduate student doing research at the USPHS Hospital and completing my PhD thesis. Being in the Commission Corps of the USPHS meant that they could send me for duty anywhere which in my post-doctoral year. However, that did not take place until I finished my thesis and I was assigned to work at the Lexington Hospital.

            During my last year as a graduate student, in 1952 to ‘53, in addition to working on my thesis on the Effects of anxiety and morphine on the anticipation and perception of painful radiant thermal stimuli, that was to be published in Comparative and Physiological Psychology, in 1954 I was assigned to work on a clinical study of juvenile drug addiction, a rapidly developing problem at that time, with a psychiatrist, Donald Gerard who was fulfilling his military commitment in the USPHS.  Also, during this period the Research Department at the hospital became part of NIMH. In June 1952 Gerard and I were transferred to New York City to continue the study of juvenile drug addiction. During this period it was not expected that one do a post-doc. The actual awarding of my PhD was at the August graduation at the University of Kentucky.

            The juvenile addiction study was unique in that our control group was non drug users who were friends of heroin addicts. Because of good contact we had with juvenile addicts we were able to find a group of adolescents who were friends of addicts but were not addicts. We originally tried to recruit juveniles who had never used heroin. We found none that had never used heroin that matched our heroin addict group. We thus changed our criterion to not currently using and who never became dependent; however, they had to be friends of juvenile heroin addicts and who lived in areas of New York with high prevalence rates of heroin addiction. This was a very difficult group of subjects to find.  It took us a year to collect 22 subjects that met our criterion. We found some interesting difference between the control and the addict group. Gerard and I were also given another role in New York and that was to help a research group at NYU get started on a social/psychological study of juvenile drug addiction.  This group, under the direction of Isidor Chein did the most complete study of juvenile drug addiction in an urban setting that was published in a book, The Road to H.  Gerard went to work with Isidor Chein and was one of the co-authors of that book. At the completion of our study I was assigned to work with Murray Jarvik at Mt. Sinai Hospital and at the Long Island Biological Laboratory, in the academic year of 1953-54 on the psychological effects of LSD. I coauthored a number of papers on the effects of LSD in humans and one on the effects of LSD on Betta Splendens Siamese Fighting Fish. Our paper was published in Science in 1956.

GK: I didn’t even know about that one!

CK: Not many people know about that one.

GK: That one, I missed; go on.

CK: So, I spent some time studying LSD and I became very much aware that people taking LSD all say that their perception is improved, and you wonder.   Well, I looked at LSD in terms of perception and they are always impaired, so how is it improved?  I think what is improved is that actually they are seeing the world more realistically, but they are losing perceptual constancies.  So, when we sit in a corner of a room, we see it as a cube; however what we are actually seeing is a trapezoidal room. Under the influence of LSD subjects often report that the sides of the room are leaning because they have lost the perceptual constancies that allow us to function in a visually trapezoidal room. It is sort of like going up in an airplane the first time and you look down and everything looks like toys and then after you fly for a while it no longer looks like toys.  So, I think that is one of the effects of LSD, it breaks down these perceptual constancies that are necessary for functioning. At the end of that year NIMH assigned me to the laboratory of Clinical Science at Bethesda, directed by Seymour Kety.

GK: Was this where you did your schizophrenia work?

CK: Yes, although I continued some of that work when I went to BU in 1959. At NIMH I did a number of psychopharmacology studies with many of them directed toward the study of schizophrenic patients. I also collaborated with Kety and Louis Sokoloff on cerebral metabolism studies in normal aged volunteers. In my participation I measured and recorded galvanic skin responses of the subjects.  I worked closely with Allan Mirsky during this period. Our experiments suggested that the primary behavioral deficit in the schizophrenic was one of inability to focus attention. This led to our proposing a hyperarousal theory of schizophrenia.

GK: Now this theory, as you well know, is persistent today and can be found in some of the presentations, even at these meetings associated with inhibitions of pre-pulse. 

CK: Yes.

GK: The blocking of pre-pulse inhibition. But what was the date that led you to this early “insighting” factor; it was one of the first, if not the first, insights that there was a breakdown in the intentional processes in schizophrenia.  What exactly cued you and Mirsky into this idea?

CK: Allan Mirsky arrived at NIMH Bethesda at about the same time as I did in 1954. Although we were in different laboratories we became close personal friends and research colleagues. The findings and the development of a hyperarousal theory of the schizophrenic was prior to my leaving Bethesda in June 1959. Allan had been researching the attention problems of petit mal epilepsy patients using a very simple but sensitive test of attention, the Continuous Performance Test (CPT). We then thought it might be interesting to see if schizophrenic patients would show a deficit on this test. The deficit seemed specific when compared to some simple test of cognitive function that did not require continuous attention. We also found that chlorpromazine in normal subjects impaired attention; however, in schizophrenics it improved attention. The question was why it has different effects in normals and schizophrenics? Our hypothesis was simple. We postulated that attention performance, as a function of arousal, was an inverted U, that is, as arousal increased performance improved, however, at some higher level of arousal, performance began to deteriorate. Thus, we hypothesized that for chlorpromazine to improve the performance of a schizophrenic patient, the patient must be on the descending limb of the inverted U, i.e., hyperaroused.  In a later experiment done in rats when I was at Boston University, we published an animal model of the hyperarousal theory in which we caused increased arousal in a rat by low level stimulation of the mesencephalic reticular formation. This resulted in performance impairment in an animal adaptation of the CPT. Under these conditions chlorpromazine improved performance of the rat while under basal levels, i.e., no stimulation, chlorpromazine impaired performance. Unfortunately, I do not believe that we impressed the Schizophrenia research community.

GK: When did you go to Boston?  Was that after that period at NIH?

CK: I left NIH in June of 1959 to take a position of Associate Professor of Pharmacology at Boston University of Medicine. Although I was happy at NIH my acceptance of the offer at BU had much to do with personal reasons. My wife, Marcia who came from Boston wished very much to return because of the illness of her father. At BU I was required to be responsible for all the lectures on centrally acting drugs. It was a great learning experience for me. When the Chairman of the Department assigned me to give the lecture on anti-epileptic drugs and I told him that I didn’t understand anything about anti-epileptic drugs, he said, “You have all summer to learn.”  So, I prepared one of these lectures.  You may have been in the same situation, when you prepare a lecture in a field that is new to you, in that one hour lecture you tell the students absolutely everything you know about a subject  and that you are afraid that you are going to get a question.

GK: Didn’t you start animal experiments at BU?

CK: Yes, I set up two laboratories in Boston, a rat laboratory at BU and laboratory for human experiments at Medfield State Hospital. However, I should regress at this point. While at NIH I started working with Joseph Cochin who was in the Cancer Institute. He was doing pain studies in rats as well as clinical analgesia studies in cancer patients. When I was at Lexington my pain and analgesia studies in humans involved the measurement of autonomic responses. When I met Joe Cochin who was doing clinical work in the Cancer Institute I mentioned that I thought I might be able to develop a non-verbal measure of pain in patients using autonomic responses. Although I spent a year in this effort it turned not to be a reliable measure. However, my year of contact with cancer patients was an important learning experience for me. One of the things I learned was that the clinical environment is almost as important as the analgesic drugs in keeping a patient comfortable.  At the Cancer Institute at NIH there were two clinical wards.  They were mirror images of each other and the same physicians serviced both wards. Assignment of patients to either ward was random. In the course of my studies I became aware that in one of the wards a lot more morphine was used than the other ward. The only difference between the wards was that one had a stable nursing service and other one did not.

GK: So, the patients with the stable nursing staff used less morphine?

CK: Yes, that’s right. It gave clinical support to my PhD dissertation findings in which I found I could manipulate the experimental pain threshold by changing my relationship with the subjects.

GK: Interesting.

CK: Yes.  This carries over in animal experimentation. If you are gentle you will get a different result then if you are not gentle. So, in Boston I set up an animal laboratory.

GK: Now, this would have been about the time you published that famous paper, or did the work on that famous paper with Joe Cochin that tolerance to a single dose of morphine can last for many months, right?

CK: Yes.  That’s right.  We started working together when we were both at NIH.  Joe’s main dependent variable was the “hot plate” pain procedure. I added a simple behavioral method to the experiments.  I measured swimming time to a goal in what you would call a “single alley maze.”  An aside is that many people thought that a critical thing was that the alley had to be 13 feet. The reason for 13 feet was that I had a counter that was thirteen feet long with the last foot hanging over a sink that allowed ease of draining. The importance of these experiments with Joe Cochin was that there was tolerance to a second dose of morphine administered months later. Also, the tolerance to the analgesic effect was more lasting than the effect on swimming. We tried to determine why there was such a long-term effect. Among the things that we entertained was that tolerance may be a type of an immune phenomenon. Actually this hypothesis was suggested in the 19th century. We tried some passive transfer experiments and some worked and some did not.  The thing was that it probably was a real phenomenon; however, it was never stable enough that would allow you to go on to the next step.  It was sort of like, you have a finding and you want to investigate it, but you always have to go back to make sure that you have the phenomenon every time you do it.  So, you always have to start at zero; you never can advance very far beyond that, because you will always have to demonstrate each time that you still have the phenomenon.

GK: But, in a sense in some of your latest work you are more or less, pursuing the same question, namely: what is the basis for these long-term effects of morphine?

CK: Yes.

GK: I mean, you have some new work with brain imaging of brain activity if I remember correctly.  Do you want to tell us a little bit about that?

CK:  I did collaborate with Dr. Linda Porrino, who at that time was a member of the Laboratory of Cerebral Metabolism at NIMH, and demonstrated that the brain does change with continued use of a drug.  The long-term effects of addicting drugs really started with my work with Joseph Cochin. These experiments that I have already described certainly suggested that there must be some long-term effects that may contribute to continued drug use. The story of a different long-term effect appears in a number of our experiments, many not related to tolerance.  The big leap on long-term or residual changes in the organism started with an interesting phenomenon having to do with brain stimulation reward that was not discovered by us. There is an old observation of brain stimulation of reward that if rewarding brain stimulation is left on, rats will press levers to turn it off.  The question that we asked was why the rat turns it off? Does it turn off the stimulus because it is the onset that is rewarding, and the rat learns that if it turns it off the experimenter will turn it back on? So, we thought we would see what morphine did in this model. If morphine raises the threshold to the onset of the stimulus it would suggest that the stimulus became nociceptive, however, if the threshold was lowered it would suggest that the animal was turning the stimulus off so the experimenter would turn it on, and it was the rewarding effect that was driving the behavior. This seemed like a nice simple experiment that answered an old question. However, something else was happening. We were using large doses of morphine, 10 mg/kg and about the third time, the first animal we studied received this dose of morphine my student who was carrying out the experiment came running into my office and said that he did something bad to the rat. He said the rat appeared to be having some kind of seizure. Well, the animal wasn’t having a seizure; what it was doing every time it got morphine, not at first, even when the stimulating current was not on, the animal would bite and chew. It was displaying a stereotypical biting behavior.  Well, this is sort of interesting and many people that worked with morphine realized that you don’t really need the electrical stimulus.  If you do repeated high doses of morphine in the rat, you will see stereotypic behavior.  So, we got interested in finding what would block this effect. We found that dopamine D1 antagonists would block this behavior. We also found in the literature that MK-801 would also block the behavior. When we found that rats receiving three 10 mg/kg doses, 24 hours apart when challenged even months after the original three doses of morphine would bite and chew after a low dose of morphine, you have to think that somehow that the brain has changed. There is no magic in the system; the brain has changed but how has it changed?  So, we thought of one way of looking at it was to use the 2-D-oxyglucose method of measuring metabolic activity in the brain. We had previously instituted the method in my laboratory in collaborative experiments carried out with Linda Porrino from the NIMH Laboratory of Cerebral Metabolism. And so, what we did was sensitize these animals with four 10 mg/kg doses of morphine in 36 hours. Six days later, to our surprise, we found that these animals showed a remarkable increase in metabolic excitation throughout the brain, in the limbic areas, and especially in the frontal cortical areas.

            Because of the possibility that the effect was due to conditioned cues, we eliminated these cues and the metabolic experiment was done in a different environment. Then, we repeated the experiment in which in one group of rats the metabolic experiment was carried out in the presence of all the possible cues and in another group of rats without the cues and we found that although both groups of animals showed changes in metabolic rates at six days, the extent of the effect was significantly greater in the presence of cues. Thus, these results strongly suggest that just drug alone will cause long lasting brain changes; however, the presence of conditioned cues will enhance these protracted effects. We were excited by these results because they clearly indicated that there could be long-term changes in the brain and these changes could be enhanced by conditioned cues. I believe experiments by the O’Brien group at Penn have shown that conditioned cues do activate areas of the brain that are altered by the abused drugs themselves. We have got some preliminary data that indicates that two weeks after the original drug treatment we still have the changes in the brains of a rat. Now, we do not know if these effects are going to be there in six months. Also, this effect in some ways related to the long-term tolerance effects I found with Joseph Cochin.

GK: Well, it does parallel the increase in biting behavior, correct?

CK: Yes, yes. We know that an animal model is not necessarily completely homologous to the natural situation.  But the data has other implications and has implications that are surprising because we find that dopamine D1 antagonists will block the effect.

GK: How are you coming throughout your career to be able to balance your clinical work with the animal work?  Did you do clinical work for a while and then animal work or did you sometimes do both together?

CK: I have done a great deal of clinical research. Most of my research was clinical in nature when I was at Lexington and it continued to be clinical research while I was in New York and when I was in Bethesda. However, while in Bethesda I did some animal research with Joseph Cochin. When I came to Boston in 1959 I set up an animal laboratory as well as a laboratory for research in schizophrenics at Medfield State Hospital and later at Boston State Hospital. However, once the deinstitutionalization movement took hold I no longer could carry out my research in schizophrenics. Although my PhD was in clinical psychology, the only time I did clinical work was when I was a graduate student at Lexington.  Some of my pharmacology graduate students at BU liked to dig up some of my early research papers in which I used the Rorschach and kid me about them. I strongly believe that my early experience with patients both at Lexington and later at NIMH was significant in shaping my research and how I looked at a research problem. It made me think more about the relevance of my experimental work. I believe, for example, that the research of the molecular biologist working on some aspect of schizophrenia would be enriched if he/she had some experience with schizophrenic patients.

            I would like to see that drug dependence researchers spend time in a drug treatment clinic. I don’t think people are aware of the severity of withdrawal with things like alcohol and the severity of withdrawal from drugs like barbiturates or even withdrawal from opiates.  Although cocaine does not seem to produce physical dependence, e.g., somatic withdrawal signs, knowledge of what that user is going through, I believe, add a positive aspect to the research. At least for me, I have always thought about the possible relevance of my experiments to the clinical situation. Thus, I believe I was lucky to have had that clinical training.

GK: Who do you think would have been the most influential on your career and directing you toward psychopharmacology?  Was it Abe Wikler or was it Harris Isbell, or a combination of both?

CK: It was both, although initially it was Isbell. He taught me a lot about doing clinical research. One of the important things I learned by being on his research team was his sensitivity and appreciation of what the subjects were going through. If he were a different sort of person I do not believe that the experiment would have been completed. Even though the severity of the barbiturate addiction and withdrawal was much more severe than had been expected, the subjects did not want to quit even though they could at any time.  Except for the first year when I worked on the chronic barbiturate experiment, I mainly worked with Wikler, although during my last year at the hospital I also was involved in a clinical study of juvenile drug users with Donald Gerard. What I learned from Wikler is to be critical of one’s own work. Challenge your experimental design. Think out of the box.  Wikler made one think through the relevance of an experimental model to the clinical situation. Isbell did not need models for he actually studied the disease.

GK: Now, this is a tough question and [in] my short career I would have trouble answering this question, but what is your favorite study?  I mean, what is the study that you think made the biggest contribution? Let’s start with that and which one do you think will perhaps have the longest or the most impact; I’d say not the longest, because who knows where we will be down the line but, so far?

CK: Well, I think, in terms of impact or long-term impact, I played a major role in understanding the reward system with opiate drugs and cocaine drugs, brain stimulation work.  And, I brought something to that field and there was a study, a first study by Richard Marcus, a graduate student, and then Ralph Esposito, in which we decided to do classic psychophysics with brain stimulation. There really was not one specific study but the series of studies that demonstrated that the driving force of drug use was the positive or rewarding effects. This was during the period when the opiate model with its severe physical dependence shaped the thinking. I remember the first time I formally presented my findings and the argument that the driving force for drug use was the positive rewarding effects. They made you, at least at first, feel good.  This was at a CPDD meeting.  Wikler was sitting in the front row. I could see him fidgeting as I was presenting my hypothesis that the driving force for drug use was the pleasurable effect resulting from activation of the brain reward system. As soon as I finished Abe jumped up and argued that continued use of opiates or any drug was its restorative effect.

GK: I think that was really a conceptual breakthrough. I know for myself that your studies were the framework for understanding that drugs really act on the reward systems of the brain and have that threshold changing effect. Obviously, this came from your pain work, but much like the effects of drug on pain to raise the pain threshold in the case of reward the threshold was lowered.

CK: It seemed obvious to me if one did psychophysics to obtain a threshold for pain that the same psychophysics should be applied to determine the reward threshold. Olds and Milner were first to report in 1954 that stimulation of certain sites in the brain were rewarding. Psychologists in studying rewarding brain stimulation found that the operant methods of Skinner could easily be adapted for the study of the rewarding effects of drugs. Although it was fairly easy to train rats in the operant procedure where the dependent variable was rate of response, I believed drug effects on reward using operant procedures could be confounded with motor effects. Thus, I decided to use a classic psychophysical model that I had used approximately 10 years earlier in the study of pain and analgesia in human subjects. A graduate student, Judy Nelsen, was assigned the problem. She was to put two electrodes in each animal, one in a reward site and one in a pain pathway. Thus we believed we could in the same animal study the effects of morphine on two different neuronal systems. We had no difficulty in placing the electrodes, but we had difficulty in training the same animal on a multiple schedule using the two procedures. At that time my colleague from my days at NIMH, Allan Mirsky, came on the faculty at BU and he was doing EEG studies in primates.  We borrowed his EEG set-up and simultaneously recorded from our implanted electrodes, one in a reward site and one in a pain site with and without morphine.  We quantified the EEG recordings and found that in simultaneous recordings of EEG from both pain and reward sites opposite effects were happening. In the pain pathway, morphine resulted in an increase in high amplitude waves and lower frequency. In the reward pathway it was just the opposite. Thus, morphine was simultaneously exciting one area of the brain and depressing another.

GK: That’s great!

CK: Although we were excited about our findings, we still had not demonstrated the difference in behavior. My next graduate student, Richard Marcus, demonstrated the difference that morphine at a certain dose raises the threshold for nociception, brain stimulation, and at the same dose lowers the threshold for rewarding brain stimulation. Unfortunately, the positive and negative stimulation were carried out in different animals. Most investigators using intracranial rewarding stimulation adopted the Skinner model in which rate of response was the dependent variable. Our group adopted as the threshold at which the “half-maximal” response rate intensity was obtained. Although my psychophysical method and the half-maximal response rate  gives somewhat similar effects there is a problem in that the maximal response rate of many drugs is not identical to that of saline. Thus, for example, the maximum rate of response with cocaine is usually greater than that of saline. Depressant drugs, e.g., neuroleptics, often have a maximum response rate lower than that of saline. Surprisingly this is often interpreted as a motor effect.

GK: How did you react when you first heard about the Old’s study?  What were your first thoughts when you heard about it, did you hear about it through the grapevine or did you see it presented or did you actually see the paper appear in press?

CK: I think I first heard about it at an American Psychological Meeting in which I also had given a paper. My first thought, I believe, was, “Where was the drive reduction?” However, I thought it was a most exciting finding. I must admit that I did not fully see the implication of Old’s experiment. Remember, the drive reduction hypothesis was quite prevalent at that time. I still believed that drug use was maintained because of drive reduction, whatever the drive was.  People only used the drug because, acutely, the first time they used it provided a kind of self-treatment.  Almost every drug addict in Lexington was diagnosed as a character disorder or depressed.  Now, there are people that certainly use drugs for these reasons, but I no longer believe that the majority of drug dependent drug individuals do so to normalize themselves. Do I believe that there are no drug users who use drugs to normalize themselves? Of course not! I believe that if we, psychologists, do not have an obvious drive, we invent one.  It has been suggested that a priming stimulus creates a drive to press the lever again that creates a drive to press again

GK: Conan, how did you stay in the field?   I mean, you have a prodigious history of publications in both the clinical and in the basic science area.   What kept you from being tempted from going into advertising or clinical psychology where certainly you probably could have made a better salary? What kept you in this field and how did you manage to do it?

CK: I think the major reason was that I enjoyed the research and never found it boring. Although I would have liked more income I really cannot complain.  I have had an NIH Research Scientist Award or its forerunner since 1959 when I came to BU. Another thing that has kept me motivated is that I love mentoring students.   They keep you on the ball and they are exciting to work with, but sometimes they are a pain in the ass, but they are exciting.  In fact, just before I came here I was thinking of how many people have come through my lab.

GK: Well, that was going to be my next question.

CK: OK.

GK You, probably of all the people I know in this college, have trained more students than anyone I know.

CK:  Now I believe there were 22 PhDs, plus two who unfortunately could not get it.

GK: Stephanie?

CK: Stephanie Raznick was one of these students and she did her dissertation in your laboratory; although her degree is from Boston University. The other student was Ellen Weinberger who did her dissertation in the laboratory of Eva Killam at the University of California, Davis. Both of these students had two mentors. Weinberger’s defense of her thesis was unique. It was held in a hotel room at a FASEB meeting in Chicago. She had people from three universities examining her. In addition to PhD students I also mentored a number of MA of Medical Science Students as well as honor undergraduate students who did a research project in my laboratory. Most of these went on to graduate school or medical school. I believe a few of these students may have ended up in your laboratory. If I include all of these students including post-docs, I probably have had close to 35 to 40 students.

GK: I think one of the most remarkable things that I think about your career is that you obviously have a form of excitement that you generate that has been catching to the student This is a very important part of the College and I don’t know how we would do that, but I think, you know, the Kornetsky ability to attract people to psychopharmacology. And, well, I think that probably more than anyone I know you have attracted people to the behavioral end of psychopharmacology.

CK: Well, one of the things I try to do is I tell them you are working on an experiment. It does not matter how simple that experiment is, you are doing something that you don’t know the answer to and hopefully something that no one else has done yet. It is something entirely new.  You have to get them excited about the research. I do not believe that most people realize that when you have trained an animal you have developed a common language with that animal.  When you fail to train an animal it means you have failed to communicate with that animal. Also, I occasionally ask them some “crazy” questions. I try to make them think. I want them to be excited about their research. Often the work itself may be tedious but the excitement is in the search.  If I do not become excited by what they do I cannot expect them to become excited.

GK: Are you happy with the way things have turned out for your career or would you have been rather a jet fighter pilot?

CK: I wanted to be a fighter pilot in World War II. I enlisted and entered the Army Air Corps, as it was called then, in March 1944.   Once in the Air Corps I was required to take a full week of tests, both performance and IQ. If I passed I would end up as a pilot, navigator or bombardier. I passed for all three and my highest score was for navigator. It was interesting; the scores given were standard scores with a mean of 5 and a standard deviation of 1. I believe I had an 8 for navigator and 7 for both pilot and bombardier. This meant I probably would be sent to navigator school. I was disappointed. It was toward the end of the war and a score of 8 was needed for any of the three flight trainings.  I was disappointed because at 18 years of age I wanted to become a fighter pilot and not a navigator in a large bomber.  While I was waiting to be sent to navigator school I was given a two week crash course on being an airplane mechanic and later a flight engineer on B24 bombers that were being used to train copilots and gunnery students. I was responsible that my plane was in flying condition every day and as the engineer I would fly with a pilot and co-pilot and a gunnery instructor and about six or seven gunnery students.  Luckily for me, I never got trained as a navigator because I found that I had a tendency for air sickness if in rough weather I could not see the horizon. Navigators sat in a small darkened area which in rough weather was a prescription for air sickness. Luckily for me the war ended in the summer of 1945 before I could be trained. I still worked as a mechanic and engineer until discharged in December 1945. The Army gave me the choice of going through training or receiving an early discharge. I took the early discharge for if I chose the training I would have to serve three years after that. That was a long answer to a simple question about being a jet pilot.  I returned to the University of Maine, Oromo, in January 1946. I had completed my first year in college as an engineering student prior to going into the service. If I had not gone into the Army I probably would have finished my undergraduate career with a degree in mechanical engineering. However, upon returning to the University I decided I did not want to be an engineer and enrolled in the College of Arts and Science. Engineering students had to work too hard!! Actually, my first choice of a major was history.  And there were a lot of reasons I didn’t go into history. One of them was that there was a small history department and the Chairman in that department and I didn’t see eye-to-eye on political issues. He believed that Roosevelt was a communist. I did not believe that I could survive in a small department with the Chair who believed that.   So, I took a psychology course and that seemed to be a field that would fill my interest in science and that seemed interesting. By my senior year I began to think that I could earn a living as a clinical psychologist.  I found that the University of Kentucky in Lexington had an approved program in clinical psychology. I applied and was accepted. I fairly quickly found that doing the psych testing was interesting but sitting with a patient doing therapy was not my forte. After the first session I found it repetitious and boring. The only type of patient I really enjoyed being with was schizophrenics. With feelings of grandeur I believed that I could cure a schizophrenic. I had read a book about that time I believe by John Rosen on treatment of schizophrenia. At the Lexington USPHS was a ward for patients with severe mental illness. Most were schizophrenic. I started spending time on the ward and with the confidence of the ignorant I believed I could cure a schizophrenic patient. I asked the ward director if I could work with a schizophrenic patient. He was most happy to give me free rein. They gave me a patient. However, they did not tell me that he was a feces thrower!  As you might expect I did not cure this patient. I would spend approximately 30 minutes with him almost every day. Although he was mute when I first started to see him after probably about a month he started talking to me. He did not make sense, but he would speak. He also stopped throwing feces.

GK: So, that was some success.

CK: I certainly did not cure his schizophrenia, but he would go to the dining room to eat.  I would do some of his crazy behavior with him. For example, the floor of the ward was cement with wide expansion crevices and he would spend considerable time trying to clean them with his finger nails. I found he liked if I did it with him. It seemed to me at that time that schizophrenia was a neurological disease.  I read Kraepelin and I thought, maybe he had it right. Dementia Praecox seemed like a more appropriate name for the disease to me.

GK: Where do you see our field is going? Obviously you have a game plan for your own research. Obviously, schizophrenia research is starting to return to the origins that you saw back when you were training, both from a dementia hypothesis and the neurological hypothesis, which are both very much at the forefront of the field right now.  But where do you think schizophrenia research is going to go if it’s really going to help people?  And, where do you see drug abuse research is going, given that we still obviously have a major drug abuse and drug dependence problem in the United States and in the world, for that matter?

CK: It’s hard to tell!

GK: Let’s start with schizophrenia.

CK: OK. Unfortunately, I lack the training to really investigate the molecular relationships to behavior. Certainly people with schizophrenia have changes in the brain but I would not know where to start without extensive additional training. So, I think we have got to learn about what are the differences and who are the vulnerable people and I have been very pleased with some of our  research on attention and CPT research, suggesting we may  be able to pick up those most vulnerable.  And not all schizophrenic, for example, have these deficits, so we are dealing probably with more than one disease so we may be able to separate out which ones have deficits and which ones do not. However, we have to be very careful when we define deficits for a disease. What we may be looking at may just be an epiphenomenon. Although we may be able to model in the rat some aspect of the schizophrenic process I do not believe we can make a rat schizophrenic.

GK: I think that is another one of your conceptual contributions that has been picked up by a number of individuals and that has to do with formulating animal models, how animal models can be validated and what they can mean. I know Mark Dyer, for example, has written and spoken on it, and a number of other investigators, about the fact that one cannot mimic the whole syndrome but can at least model in a predictive way one symptom of the disease.

CK: The major difficulty is that it is difficult to overcome dogma. An example: I did some experiments at NIH that seemed to suggest that schizophrenic patients have an attenuated response to amphetamine. This of course was completely counter to the belief that amphetamine exacerbates schizophrenia.

GK: Yes, right, I remember that.

CK: We didn’t know what to do with it; we never published the work at that time.  Then, in the late 1960s when I was at BU and had a laboratory at Medfield State Hospital, the dopamine hypothesis was popular. A major support for the hypothesis was that schizophrenia symptoms were exacerbated when the patients were administered amphetamine. And there I was sitting on data suggesting the opposite.  In fact, Allan Mirsky and I thought that if schizophrenics have an attention deficit disorder, amphetamine may have a positive effect. I proposed such an experiment to the hospitals review committee, the equivalent of an IRB. They would not approve the experiment. They said I could do a brief pilot experiment. In this pilot experiment we gave 20 mg of d-amphetamine or placebo each night at 8.00 to a group of chronic schizophrenics and by observation rated them as asleep or awake. This was done by nurses who were blind as to the treatment.   Of the nine patients the following effect was obtained: with d-amphetamine compared to placebo, three slept slightly more, three slept slightly less and three showed no change.  Twenty milligrams of amphetamines, which is not a minor dose, given at eight o’clock at night would probably have significant effects in non-schizophrenics. I never did anything further because of the difficulty to do research in a mental hospital because of deinstitutionalization. Also I was focusing more on drug abuse at that time because of the difficulty of doing research with mental patients. I did not publish that finding until late in the 1977s in the Archives of General Psychiatry. Danny Freedman was editor at that time.  I did not follow up on these findings, mainly because no one paid attention to anything that questioned the dopamine hypothesis.  Advancement in any research area depends greatly on having an open mind. Researchers need not to be afraid to pursue a problem or an idea that is contrary to current thinking. The risk may be great, but you might find something that is not just more of the same.  The same holds for drug abuse research. The best example I can think of is the experiment by Wikler, published in 1952 in the Psychiatric Quarterly,  in which the subject is allowed to have any drug in the formulary; he allowed an addict to self-regulate morphine use. The subject had been a long-term user who had been “cured” of his addiction many times.  The main problem with drug addiction is that it is a complex behavior. It is a social, psychological and economic problem. In the inner city population of Boston, 18-20% of youngsters are out of work. How do they get their kicks besides killing each other? A lot of people try drugs and don’t continue into addiction. In my study of teen age drug abuse I did with Donald Gerard in New York City in 1952 and ‘53, we went looking for teenagers that were friends of addicts and had never used heroin. It was a hopeless task. We found many teen agers that were not, or had never been addicted, to heroin but all, at some time had tried heroin. We quickly changed the criterion for our control group from never tried to was not a user and never had been a regular user of heroin.  Other people, like me for example, had been a subject of an experiment. Frank Frazier at the Lexington Hospital was doing an experiment in which he compared post addicts to a control group and I was one of his control subjects. We were administered 20 mg of intramuscular injected morphine. That is a pretty large dose. Although I found it pleasant and enjoyed the whole day, I never wanted to repeat the experience. Why didn’t I want to repeat the experience?  I didn’t like the loss of control and, more important, I get my kicks other ways. The main thing about drug abuse is that it becomes biological when people take the drug, but there are people that are more vulnerable, but the vulnerability may not be a biological vulnerability.  An interesting thing about research in drug abuse is that it has become a vehicle of understanding of brain function and behavior. I think that we would not have the understanding of the brain reward system and the role it plays in normal behavior if we did not have the model that drug addiction and drug effects on the brain give to us. The system is not just there so that we can have pleasurable effects from the addicting drugs, but it has to do with all positive feelings and its absence may have an important role in understanding many pathological states.

GK: And, this will probably have major impact, I would just guess, for affective disorders and for other mental disorders the College is much interested in.

CK: Well, people have to have their mind open and a number of years ago I organized a workshop at the College with a former student of yours, Neal Swerdlow, on the role of dopamine in depression.  I am trying to think of who the other person was. I believe he was from Vancouver.

GK: Fibiger?

CK: Yes, Chris Fibiger. We felt that dopamine is certainly involved in pleasure, because if you don’t have dopamine then maybe you don’t have much pleasure.  And, there were a couple of drugs out there that were dopamine agonists that we used and historically people use amphetamine for depressed patients and, in fact, they still do.

GK: They still use methylphenidate.

CK: Yes, It is of interest that many people briefly looked into the session. However, the audience was very small and most was hostile to the idea.

GK: Why?

CK: Because it went to the contrary to what was the “thinking.” Now, we could have been completely wrong, but that’s beside the point.  I think that drug abuse research will have relevance for depression and mania.   If you take cocaine and gradually increase the dose you will have a model for a manic patient.

GK: Absolutely.

CK: A slightly manic person is a lot of fun; somebody with a little cocaine is fun and somebody with a lot of cocaine is not and somebody that is very manic is not much fun at all.

GK: Right, I think that is a very good point.  Well, my last question for you would be, what about the College?  Where do you see this College of Neuropsychopharmacology going?  What do you think they should be doing, perhaps, that they are not doing?  Obviously, you and I share concerns about training and the need for the continuation of influx of fresh young people into the College and that is, of course, one of the goals of the College over the last few years.  But, what else would you see as an important issue that the college should be addressing?

CK: Well, the College should never lose sight of the fact that it is a major multi-disciplinary organization.  And if it becomes and moves too much in one direction or the other, it will be in trouble. A lot of the basic science in the field has become very molecular.  Now, as people say, you can’t even have a thought without molecules changing in the brain.  There’s no magic up there.  And, so, we can’t become overboard one way or the other.   We have to keep a balance in this organization and that includes more integrated types of panels.  By integrated, I mean, not all the molecular here, and then all the clinical there; we have got to get the clinical people going to the molecular people and the molecular people have to explain the non-molecular scientist that they can understand the significance of their findings.  I am sometimes on a PhD student’s graduate committee whose thesis is very molecular. If I do not understand much of the thesis, I try to get them to explain it so I understand its implications, etc.  If after a few questions they still don’t explain the significance in a way I can understand the problem I think there is a problem. I have always felt that any discipline needs to be able to talk to the reductionist at least one step below it and to the expansionist at least one step above it. I think it is important that we maintain the original intent of the organizing committee of ACNP that we maintain ourselves as a multi-discipline organization and not an organization of multi-disciplines.

GK: Thank you, Conan, I think that was really…

CK: I enjoyed talking, as I always do.

GK: Enjoyable discussion. 

Thomas A. Ban’s interview with Conan Kornetsky,  conducted in San Juan, Puerto Rico, on December 10, 2003.

CK: I was born in Portland, Maine, on February 9, 1926, the third child of Alex and Ida Kornetsky. My siblings were a sister, 12 years older and a brother 14 years older. Due to an error by the obstetrician my mother died a week after my birth. During the first year of my life we lived in a large three-family house with the families of my mother’s two sisters. After a year my father gathered up our family and moved to Chelsea, a suburb of Boston. Because he could not take care of me and work I was boarded out to another family. After two years my father remarried and we were all together once more.  This lasted for a couple of years before my step-mother died of cancer when I was in kindergarten. From that time until I finished third grade I was a “latch key child.” During those years, during the depression, we moved every year around Boston because landlords would give you 12 months to live in an apartment for 11 month’s rent; moving was a great savings. I did kindergarten through third grade in the Boston area; my sister graduated from high school and my brother from the Massachusetts school of optometry. But, my father could not find work in the Boston area. My sister went to live with one aunt in Portland, I with an aunt and uncle who had no children. My brother took a job in northern Maine with an optometrist and my father found a job in a shoe factory in Auburn, Maine. I stayed with my aunt and uncle through high school. Although they tried their best I was not a happy child. They correctly saw me as difficult. I loved to read but was not a good student.  I was fairly independent.  I loved history, mathematics and science but I didn’t do well in those subjects. I used to argue with the teachers and if you disagreed with the teachers, you were thrown out of the classroom and had to spend time in the principal’s or Sub-Master’s office. The Sub-Master and I became very friendly; he used to get me back in the classroom and worked out some apology with the teacher. 

TB: When did you graduate?

CK: I graduated high school in 1943 and entered the University of Maine in engineering in June.  World War II was on, so I tried to get time in college before I went into the service.

TB: How old were you when you graduated?

CK: I was 17-years-old and did one year of college by January 1944. Then I was inducted into the US Army-Air Force in March. I was supposed to train as a navigator but due to cut backs they gave me temporary training as an engineer on B24 bombers while I was waiting to be trained as a pilot or a navigator. When the war ended, they gave me a choice of early discharge or pilot training with three additional years in the service. I decided that was not a good choice, so I was discharged.

TB: When were you discharged?

CK: In December 1945 and I went back to the University of Maine in January 1946.  I decided I didn’t want to be an engineer, so I went into a liberal arts program and decided to look into various fields. I took a lot of philosophy, history and psychology; [I] found psychology and philosophy the most interesting and received my degree in psychology in 1948.  I had a number of interviews but couldn’t find any job that was satisfactory. At that time the GI Bill would pay for further education; first I thought I would go to graduate school in philosophy. Then I decided I would not be able to earn a living if I did that, so as a second choice I thought clinical psychology would be interesting. I had taken an intensive course in testing that certified me as a mental tester. I had also taken a course in abnormal psychology in which we visited a local state hospital a number of times where patients with different diagnoses were presented. So I looked into the American Psychological Association’s listing of approved schools for clinical psychology.

TB: What did you find?

CK: The only school approved in New England was Yale. Approved schools elsewhere were all first rate, but I was not that good a student; I had a mixed academic record in college.  I did very well in courses I liked but in courses I didn’t like I didn’t care what grade I got.  Also, I was very active politically after the war.  I was a member of the American Veterans Committee, which was a radical leftist group.  I was more interested in politics than grades. I had a professor of philosophy and religion and we used to go to a local pub and argue. His aim was to prove that God existed and my aim was to prove God did not exist.  Every paper I wrote for him was to prove that. We had a great relationship and he said, “See if the University of Kentucky is an approved school.” He used to teach there and wrote me a good recommendation. So I applied and with his recommendation I was admitted into the clinical psychology program.

TB: When was that?

CK: I arrived in September 1948.  I had the GI Bill but after a few weeks I wanted to find an additional source of funding.  The GI Bill paid for books and tuition, plus a stipend. I got a job in a sorority house as a house-boy, a glorified janitor. But then the Chairman of the Department told me there was an opening for one student in the Clinical Psychology Department at the US Public Health Hospital in Lexington, Kentucky.  This was a hospital for the treatment of drug addicts.  At that time I did not know what a drug addict was and the only drug I knew about was alcohol.  I didn’t know anyone who used marijuana. However I had to make a choice, sorority house or a mental tester; so I took the job as tester.  The stipend was board, room and laundry, so I would live at the hospital. The Lexington USPHS Hospital was also a prison for the incarceration of addicts. It was a great experience living there. My room was a cell similar to the cells of the prisoner-patients.  The only difference was that I had a key to my cell.   I didn’t have a car, but transportation was fine. It was five miles from the University. There was no trouble getting back and forth during the day, but in the evening I was stuck there, so I used to study and hang around and chat with the prisoners who would tell me all about drug use.

TB: That had to be interesting.

CK: I found the most interesting place to hang out was the research ward.  I spent time talking to the patients and learned what experiments they were on. I was learning a lot; I don’t know if I believed all the stories, but they were interesting.  The director of research was Harris Isbell. He would make rounds every evening and he kept seeing me there.  After he learned who I was he would tell me about the experiments including a new clinical experiment that he was planning on chronic barbiturate intoxication.

TB: This was what year?

CK: The fall of 1948.  At that time it was not known there was physical dependence to barbiturates. They knew there were sometimes convulsions and seizures, but no one had ever demonstrated if that was withdrawal or intoxication.  So he was planning to do a study.  Because he had no psychologist he asked me if I would be willing to participate.  My main job was that every afternoon, I would do three Wechlser IQ tests on patients and write them up.  I still had to do that, but I started to participate in the study.  This was pretty heavy stuff for a first-year graduate student. I knew IQ testing and a few new tests that I was picking up in graduate school. As a first-year student I was pretty skilled in IQ testing. I developed further one of the sub-tests on the Wechsler so we could use it repeatedly. It was the Digit Symbol Substitution Test. What I did was to change the code every time they took the test. Although there would be a practice effect, there was no learning of the number-symbol code. I probably broke all sorts of copyright laws. I also used projective tests that I was learning to use that were popular. There was a resident in psychiatry participating and Dr. Isbell, a technician and myself. I was basically the third professional, the psychologist on the project, which was great.

TB: It was your first professional experience in research?

CK: That was my first professional experience as a researcher. I spent most of that year participating in the experiment and writing my results. During that year I learned a great deal about the behavioral and pharmacological effects of addicting drugs.  One of the missions of the Research Department was to test new drugs for addiction liability and physical dependence, as well as analgesic potency. They never found one, but that was the mission. Nathan Eddy from the National Research Council would come periodically with a bag full of new drugs to try on patients. These were prisoner patients who would volunteer. They would be given drugs under controlled conditions and were followed very closely to determine if physical dependence developed.

TB: How many subjects were included in a typical experiment?

CK: There were a few subjects in each experiment. There were six in the barbiturate experiment.  One of them quit.  What we found was that besides continuous intoxication, during abrupt withdrawal from daily administration, all the subjects had convulsions or a psychosis.  That was the first demonstration there was physical dependence to barbiturates and it was the first publication with my name on it: Isbell, Altschul, Kornetsky, Eisenman, Flanary and Fraser in the Archives of Neurology and Psychiatry, 1950. Isbell urged me to write a separate paper giving more details of my results. I did, turning in a hand-written manuscript of about 100 pages. Well, my section covers two published pages in the original paper. Isbell was very kind; he taught me how to whittle it down and it was published as a separate paper. He insisted that for my career it was better if I will be the only author. The title of the paper was Psychological Effects of Chronic Barbiturate Intoxication. It was published also in the Archives of Neurology and Psychiatry in 1951. It was all heady stuff for me.

In June of 1949 I was married to Marcia Smargon in Boston. Marcia and I were classmates at the University of Maine. During the academic year 1948-1949 she was a graduate student in social work at Boston University.  By time I returned to Lexington with my bride Abe Wikler had returned from his year-long sabbatical. Because the stipend of board, room and laundry was no longer applicable now that I was married, Harris Isbell hired me as a technician from money he didn’t need for an animal caretaker. So I would be paid from now on as a technician and was hoping that I wouldn’t have to do anymore IQ testing.

TB: So you had enough from IQ testing?

CK: I was getting disenchanted.  One of the things I was trying to do was psychotherapy, but I found I didn’t like it.  I found it interesting at first, but by the third time I saw a patient, I was bored. My wife still didn’t have her degree, but she got a job in the child guidance clinic as a social worker with the professor of clinical psychology. This was probably good for me. My first contact with Wikler did not create the impression I would have liked.  Although Dr. Wikler had been back from sabbatical for only a couple of weeks he had already started experiments in which he measured autonomic responses and reflexes in dogs after drug administration. These were recorded on smoked kymograph paper stretched between two “drums.” A stylus operated   through changes in air pressure that would move the stylus back and forth on the smoked paper. He would later shellac the paper to make a permanent record. In the course of this process these paper loops were hung on pegs outside his office and until they were shellacked they were vulnerable. I came bouncing into his laboratory to meet the famous Abe and when I inadvertently brushed against some of the smoked paper loops, I heard a scream from Abe, “who the hell is this stupid ass?” That was my first contact with Abe, who later became my close friend, mentor and colleague. After he realized who I was and that I wasn’t stupid, we became very close friends. Another person came on the research staff in the summer of 1949, a psychologist named Harris Hill. Isbell assigned me to work with Harris Hill and we did some early studies on anxiety, analgesia and morphine. Abe would run an informal morning seminar. So every morning we would meet over coffee and he would give the seminar.  We would have discussion groups deciding on experiments; that is where I proposed what I thought was the greatest experiment in the world. It was probably the proposal I’m most proud of because it was a very early demonstration that environmental factors could affect the way a drug acted.  What I proposed was a simple reaction time study in which we would change the motivation of the subject during the reaction time. The hypothesis was that changing the motivation of the subject would alter the way morphine would act on reaction time.  I proposed this and Abe had a way of quizzically looking at you and the more he looked the more stupid you felt. Finally, Abe was very direct and said it was a stupid idea. The master had spoken, but a week later he bumped into me in the corridor and said it was a great idea; but we had to change it a bit.  We did the experiment and it turned out as I predicted. In the presence of anxiety precipitated by a situation in which the subject did not know whether he would receive the punishing electric shock until the “go” light appeared, behavior became disorganized and reaction time was slowed. That led to a series of experiments in which we measured pain threshold under different environmental conditions, with and without morphine. I spent three years doing those experiments with Abe and Harris Hill. My dissertation was on the effect of morphine and the role of environmental factors on the perception of pain.    

TB: What did you use for producing pain?

CK: Radiant heat on the forehead and I measured pain threshold using classical psychophysical means, which hadn’t been done before.

TB: So you studied the interaction of environmental factors and morphine on the perception of pain?

CK: By manipulating the environment just prior to the experiment. Basically it consisted of establishing rapport with the subject by spending about 15 minutes prior to the experiment in friendly conversation. We did a whole series of experiments, but mine were unique because I measured autonomic responses, verbal reports and used classic psychophysical means. That was my PhD dissertation.   Abe was the director of that dissertation but because he did not have a faculty appointment at the time, he was not the one who signed off on the thesis.

TB: When did you get your degree?

CK: In 1952, and then I moved on.  At the time I was doing my dissertation I was involved in other experiments. There was a big increase in juvenile drug addiction and a young psychiatrist, Donald Gerard, came to Lexington.  He and I were assigned to study juvenile drug addicts; we did for about a year and a half.  Then it was decided we had to do a follow-up study in a large urban area and we picked New York. So, in the fall we moved to New York and we studied juvenile addicts in 1952 and 1953.  We probably did the first controlled study of juvenile addicts; it was interesting because our control group consisted of friends of addicts.  The big problem we had was finding friends who were not addicts themselves. It took us a year to get 22 “friends.”

As Dr. Gerard and I were the so-called experts on drug addiction, having been at Lexington, we were asked to help Dr. Isidore Chein in the Department of Social Relations at NYU to get started on a big NIMH sponsored study of juvenile addiction that led to the book, The Road to H. Don Gerard, after our year of study of the friends of juvenile drug addicts, took a position with Chein and was one of the co-authors of the book. That is probably the best social psychological study of juvenile addiction in a large urban area. The book starts out with the sentence: “H is for Heaven, H is for Hell, H is for Heroin.” During my last year at the Lexington Hospital my status changed. At that time I was an officer in the US Army reserves and when the Korean War started I was called to active duty in 1944-1945.  Because I was not eager to go into the Army again, Harris Isbell had me transferred from the Army to the USPHS commissioned corps which was still part of the armed forces, a hold-over from WWII.

TB: What did you do after the completion of the juvenile addiction study in New York?

CK: At the completion of the juvenile addiction study I was asked to spend another year in New York to study LSD with Murray Jarvik at Mt. Sinai Hospital and with Harold Abramson at Long Island Biologic Laboratory.  Then, in 1954, I moved to NIMH in the intramural program at Bethesda. I was there from 1954 to 1959 in Seymour Kety’s Laboratory of Clinical Science.  In the laboratory next to mine was Julius Axelrod.  In fact, I needed some temporary lab space at one time and Julie had a little space he allowed me to use. Anyway, I did a series of studies on the effects of psychoactive drugs on performance.  First, I studied the effects of chlorpromazine, analgesics, barbiturates and opiates in humans.  I also did sleep deprivation studies. Some of those I did with Alan Mirsky. He and I developed a hyper-arousal theory of schizophrenia, namely that the schizophrenic was in a state of hyper-arousal and not hypo-arousal due to a filtering problem. The idea came from studies performed in the mid 1950s to the 1970s, working with the Continuous Performance Test (CPT) in which I found that amphetamine did not improve performance of subjects who were functioning at full capacity. Their performance was actually impaired by amphetamine.

TB:  Could you tell us something about the CPT?

CK: The CPT was a straight vigilance task. Random series of letters were presented on a screen at a constant rate and the subject was required to press a simple lever whenever an X appeared.   You could make it more difficult, by requiring pressing the lever for the X only if it follows an A. During the 1950s the only effective drug for the treatment of schizophrenia was chlorpromazine. We found that chlorpromazine would impair performance on the CPT, but not on the DSST [digit symbol substitution test].  We would then compare the findings with chlorpromazine with the effects of a barbiturate.  Barbiturate produced no impairment on the CPT, but a clear impairment on the DSST.  It was a clear dissociation between these two tests in normal subjects.  We then went on to study schizophrenic subjects.  We found that schizophrenic subjects performed as well as normal subjects on the DSST but were markedly impaired on the test of attention, the CPT. Mirsky and I were lucky at that time because the schizophrenics we studied had not been chronically receiving neuroleptics.

TB: Didn’t you do some studies with amphetamine in schizophrenics?

CK: Much of the work I did with amphetamines in schizophrenics was after I came to Boston University in 1959. During this period I administered single doses of d-amphetamine to chronic schizophrenics and I did not see any exacerbation of symptoms. I started measuring blood pressure effects and I kept pushing the dose up and finally at 40 mg of amphetamine, I had to stop because of increased blood pressure.  There were no other effects.  Our CPT studies with Alan Mirsky had already demonstrated that a major deficit seen in schizophrenics was the trouble of focusing and filtering stimuli. Since in normal subjects amphetamine allows you to filter and focus, I thought it might improve behavior in schizophrenics. So I proposed, at Medfield State Hospital, an experiment in which I would chronically administer amphetamine.  Harry Freeman, Director of Research, was all for that study.  However, the committee that was equivalent to present IRBs was not enthusiastic. They said I would have to do a pilot study before they would give permission for a more elaborate study. They allowed the administration of 20 milligram of oral d-amphetamines to the subjects in the evening.  Although they predicted that the patients would be climbing the walls, they gave permission for one week with a cross-over to placebo for the second week. Half the subjects received the amphetamine the first week and a placebo the second week. It was reversed for the other half of the subjects. Although we were interested in sleep behavior we did not have the facilities to monitor sleep. We had the nurses, on the hour, observe each subject and score them with a plus (+) if they appeared to be sleeping and with a minus (-) if they appeared not to be sleeping.  I did not want the nurses to ask if they were sleeping. One of the subjects quit, so I was left with nine subjects.  Compared to placebo there was no difference between the treatments. With amphetamine three subjects looked like they were sleeping more, three looked like they were sleeping less and three showed no change.  They certainly did not exhibit a potentiation of their schizophrenic symptoms or exhibit excitation from the amphetamine. The nurses reported no difference in behavior when the subjects were administered amphetamine. Whether they had shown any cognitive or other improvement I don’t know.

TB: You said this study was done after you returned to Boston.

CK: This was the late 1960s.  In 1970 when I presented these data nobody paid attention to it. I asked Danny Freedman, who was the editor of the Archives of General Psychiatry, if he was interested in publishing this paper, so in 1978 the paper was published with the title Hyporesponsivity of Chronic Schizophrenic Patients to Dextroamphetamine. As before, nobody paid attention to it. Getting back to chlorpromazine, my question was how could schizophrenics get better if the drug decreased arousal that would impair normal people. Allan Mirsky and I postulated an inverted U hypothesis of arousal so that where you are on that curve determines your response to amphetamine. We plot along the abscissa the arousal level and if the normal person is on the ascending side of the inverted U and you administer amphetamine it results in an increase in arousal. If the person is on the descending side of the U, over-arousal, then amphetamine would move him further on the descending side and cause a decrease in arousal. Thus amphetamine has the same basic pharmacological effect in normal subjects and schizophrenics, moving both to the right, increased arousal; however, the actual response depends whether you are on the ascending or descending leg of the inverted U. If you are on the left side of the peak, and you are given a drug, you become impaired. Since schizophrenics are over the hump, if you give them a drug they do better. Now that is an over simplification. But our belief was that there are some schizophrenics who are like that; and that there is a filtering problem. I did a number of studies with Marissa Orzack in the 1960s and showed that some first-degree relatives of schizophrenics responded in the same way as some schizophrenic patients. The nicest study was that of Gerry Wholberg. He was a psychiatrist and a research fellow at Boston University. The question he asked was whether our findings are dependent on a state or a trait. So, he took patients on medication and in good remission and gave them the CPT test. First, he did not find any impairment on the CPT. Then he decided to do the test in a situation in which the patients were distracted by a noise. He did this in schizophrenics in good remission and with normal subjects after he did a recorded interview. He found that schizophrenic patients, exposed to an interfering noise, did not do well on the test. They were holding jobs, functioning people out in the world in good remission, yet they showed impairment when he added the noise because they couldn’t filter well. I thought that was a fantastic study. Yet for some reason, nobody paid much attention to the findings. I believe because it did not fit with the main stream of thinking at the time.

TB: Did Gerry Wholberg follow up his findings?

CK: Gerry left and took a job as Director of Clinical Training at Boston State Hospital when one of his residents saw a paranoid patient who left against medical advice. The patient returned and wanted to see the resident. When the patient was alone with the resident he pulled a gun out of his pocket and pointed at him. They were in a room with a small window in the door. When a nurse saw the gun she called Gerry. Gerry felt responsible because it was his resident and went in the room. He talked for three hours with the patient. Finally, when he thought the patient was about to give up the gun, the patient pulled the trigger.  The bullet hit him in the head. He lingered for a month before he died.

TB: Why didn’t you follow it up?

CK: I was having trouble getting funded for my schizophrenia research.  They just weren’t funding it, so I focused on the drug abuse.  I was mainly interested in tolerance and did a lot of work with Joe Cochin on single dose tolerance. Our argument was: once you experience a drug, there is going to be some residual tolerance.  There was a study done when I was in Lexington by Frank Frazier in which he found that drug addicts, six months after their last dose, show tolerance to a single dose of morphine. He needed normal volunteers for his study, so I volunteered and as a subject received a single dose of 20 mg of morphine intramuscularly. I must admit that I got a high on it.  I really liked it.  However, I didn’t want to try it again because I didn’t like the loss of control.

TB: Would you like to say something about your recent research?

CK: I’m interested in two things, aging and opiates and have been working in these two areas for two years now. I’m working on the effects of analgesics on the reward system in aging.  The general belief is that older people need less morphine to produce the same analgesic effect.  I don’t believe that and my findings are in the opposite direction. I have a small grant to do preliminary work; that is coming to an end and I am writing grants to do more in this area. I am very interested in this research. I think research with analgesics is very important and I also think older people are under-medicated.  I’m also working with alcohol. I am still active.

TB: What would you like to see happen in your area of research in the future?

CK: As I grow older I am bothered by some of the things I hear. I would like to see more attention paid to science and less to money. What is driving science now is not the excitement, but something else and that is bothersome.  I get excited when I see something new.  I love it when the students get excited looking at data.

TB: On this note we should conclude this interview with Dr. Conan Kornetsky. Thank you, Conan, for sharing this information with us.

CK: I enjoyed it.  Thank you, Tom.

 

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June 6, 2019