AddictionVolume 98, Issue 7 p. 875-882 Free Access Conversation with Conan Kornetsky First published: 17 June 2003 https://doi.org/10.1046/j.1360-0443.2003.00423.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In this occasional series we record the views and personal experience of people who have specially contributed to the evolution of ideas in the Journal's field of interest. Conan Kornetsky PhD, is Professor of Psychiatry and Pharmacology at Boston University. Beginning at the dawn of the era of psychopharmacology, his work has spanned more than 50 years. He is among the last of the scientists who began their research in our field at the Addiction Research Center at Lexington, Kentucky. STARTING OFF A: Conan, can you recall for us what first stimulated your interest in science? CK: Actually, my earliest interests were history and what made things work. If genetics determines one's interests, the former probably stems from my maternal grandfather, who was a rabbi, and the latter from my father, whose primary position was the maintenance of the machinery in a shoe factory. But in spite of my passion for reading, and my father's repeated admonishment, ‘Remember, anything you put in your head they cannot take away from you’, I was not a particularly good student. In fact, when I graduated from grammar school, in Portland, Maine, the teachers recommended that I do not take the college preparatory program in high school. However, my family did not accept that advice. After high school I attended the University of Maine. Despite some family pressure to take a premed course, I decided that engineering was the field for me. Upon completing the first year of course work I enlisted in the Army Air Corps Air Cadet program in March 1944 to be trained as a pilot or navigator. When the war ended I was offered the opportunity to complete flight training or to receive an early discharge. It was not a difficult decision. I was discharged from the Army in December, 1945, and returned to the University of Maine 2 months later. ‘. . . father's repeated admonishment, “Remember, anything you put in your head they cannot take away from you”. . .’ A: And your career plans at that time? CK: I had decided that I really did not want to become an engineer, so I switched to the college of arts and science. I found the history department much too politically conservative (I was very active in the liberal American Veterans Committee), so I sampled courses in psychology, philosophy, and sociology, finally settling upon psychology as a major. My most influential professor was A.D. Glanville, who instilled in me the appreciation of psychology as an experimental science. Through Glanville I can trace my vocational ancestry to Wundt, the father of experimental psychology. Glanville was a student of Tichner, who was a student of Wundt. A: Was there any clinical element in the training? CK: A major influence on my thinking resulted from a course in abnormal psychology. We made weekly visits to the local state mental hospital for most of a semester. Patients exhibiting the classical signs and symptoms of various mental diseases were interviewed in our presence. What impressed me the most was that many of the schizophrenic patients appeared to be suffering from some sort of neurological disorder, characterized by lots of stereotyped movements. Remember, this was approximately seven years before the advent of the neuroleptic drugs. When I later saw patients with neuroleptic-induced tardive dyskinesia I remembered the patients that I saw in that state hospital in Maine. A: Did you at that time have opportunity to get into any experimental work? CK: Yes. The first independent experiment that I carried out as an undergraduate was related to focusing attention. I studied the effect of auditory distraction on learning nonsense syllables. Also, because of my liberal leanings, I did a senior research thesis that looked at social attitude. Because there was no possibility that I would be elected to Phi Beta Kappa, I decided to compare all the seniors elected to Phi Beta Kappa with those elected to Tau Beta Pi, the national engineering honor society. I found significant differences between the groups on all the social attitudes scales. As you might expect, the most liberal were the female, followed by the male Phi Beta Kappa students, and most conservative were the Tau Beta Pi students. I attributed the results to exposure of the Phi Beta Kappa students to more liberal ideas in their course work than that of the engineering students. A: Was this the beginning of your interest in experimental psychology? CK: Well, I certainly found doing these small research projects exciting. I still had no idea what I wanted to do. I interviewed for jobs my senior year but none interested me. I still had some GI Bill educational benefits left so I thought I might go on to graduate school. I had taken a course in IQ testing and had a certificate that I was competent to administer intelligence tests so I thought that clinical psychology might be a good career goal. A philosophy professor, Dr Virtue, with whom I was friendly had previously taught at the University of Kentucky, suggested I apply there. I applied and that is where I was accepted. TO LEXINGTON A: At that stage you made a link with Lexington? CK: During the first few weeks I was at the University, a position opened at the US Public Health Service Hospital at Lexington for a student to conduct IQ testing on patients. The stipend was for board, room and laundry. The hospital was also a prison for both the incarceration and treatment of drug addicts. The room I was given was similar to those assigned to prisoners, including the iron bars; the only difference was that I had a key. I was required to administer and score three IQ tests a day, 5 days a week. It was a tremendous learning experience. I knew little about drug addiction. Even marijuana was foreign to me. When I was in the army and at college the drug of abuse was alcohol. A: With whom were you working when you first went to Lexington? CK: I worked for Mary Daingerfield, Chief of the Clinical Psychology Department. She was a wonderful woman who taught me a lot about testing. Finding that I could not spend all my time in the evenings studying, I began to spend a fair amount of time in the Research Department of the Hospital which later became the Addiction Research Center. There I became friendly with the patients who were subjects on research projects. Harris Isbell, who was Director of Research, would make evening rounds and he become aware that I was often there, sitting and talking to the patients. He became friendly with me, explaining to me the research that was going on. At that time he was planning a clinical experiment on the effects of chronic barbiturate administration and there was no psychologist working in research. I guess he liked me, because he asked me if I would like to participate in the experiment. Unfortunately, at that stage of my training, I did not have the experience or the experimental resources in the types of procedures that, retrospectively, I would have liked to use. However, I used tests that I knew, and some, like the Rorschach test, that I was still learning how to use. A: How did you manage to keep up with your graduate studies at the University of Kentucky while working at the hospital? CK: Actually, I did not. Because my stipend at the hospital was for doing the clinical IQ testing, the only way I could participate was to stop going to classes. It did not take long before I received a letter from the chairman of the psychology department putting me on probation. By then I had decided I really wanted to be a research psychologist, not a practicing clinical psychologist, so I quickly got my grades up. But I should say that the clinical training and the contact with all types of patients, including the schizophrenics back at the hospital in Maine, had a major impact upon the way I would think about a problem. A: That barbiturate work was published? CK: We presented the first report of the results at the Federation of American Societies of Experimental Biology (FASEB) meeting in March 1950, with a full publication in July, 1950, in the Archives of Neurology and Psychiatry (Isbell et al. 1950). It is the first published paper that has my name on it. In 1951, I published a detailed report of the psychological studies that I conducted as part of the Isbell experiment (Kornetsky 1951). A: Who was on the research staff at Lexington when those early studies on barbiturates were carried out? CK: In 1948/49 the research staff consisted of Harris Isbell, Ann Eisenman, a biochemist, Sol Altshul, a psychiatric resident, Harold Flanary, a senior technician, and myself. Also, there were a number of very competent aides. Abraham Wikler returned from sabbatical leave in June 1949, while I was on vacation. H. Frank Fraser and Harris Hill also came that summer of 1949. I should say that I returned to Boston at the end of May to marry Marcia Smargon, who I had met at the University of Maine. Marcia was attending the graduate program in social work at Boston University and she found a job in Kentucky at the Lexington Child Guidance Clinic. The clinic was directed by Graham B. Dimmick, one of my professors at the University of Kentucky and a very competent teacher and clinician, who taught me a great deal about psychopathology. When I told Harris Isbell that I was getting married he found the funds to put me on salary, so I stopped doing IQ tests. Although I still had much to learn about drug addiction, the year I spent living at the hospital was a fantastic learning experience. The professional staff treated me as an equal and most of my evenings were spent learning about the life of a drug addict from the patients. A: Around this time you met Abe Wikler? CK: As I mentioned, Abraham Wikler returned from sabbatical while I was away. I had heard all about Abe and could not wait to meet him. Our first meeting was not particularly auspicious. Although Abe had only been back a few weeks he already had some animal experiments under way in which he was recording autonomic reflexes on a smoked kymograph. These long loops of paper were left hanging until they could be fixed with shellac. If you brushed up against them before they were shellacked you could destroy the data recorded on them. Well, I walked into Abe's laboratory all enthusiastic to meet him; however, I was not too careful and I brushed up against some of his kymographs. There was a screech and yell. I remember it as, ‘Who the hell is this stupid ass!’ Thus, I met Abe Wikler. Despite that first contact we became fast friends and he became my most important mentor. ‘There was a screech and yell. I remember it as, “Who the hell is this stupid ass!” Thus, I met Abe Wikler.’ A: Did you work with Wikler? CK: At this time, the summer and fall of 1949, Isbell thought I should work with Wikler and Hill. Wikler, Hill and I met over coffee most mornings at 8:00 o’clock. It was Wikler's informal daily seminar where research ideas were proposed and discussed. Sometimes there were simple philosophical discussions not related directly to proposed experiments or interpretation of experiments that we, or others, had conducted. At one of our early meetings I proposed what I thought was a major experiment, for it would test the hypothesis that a drug effect could be altered significantly by altering the experimental conditions, something that we had begun to discuss. Although at the present time this is a fairly well-accepted concept, especially for centrally acting drugs, in 1949 it was somewhat radical. This experiment was the forerunner of a whole series of experiments demonstrating that the drug effect could be changed by simple manipulations of the environment. In this experiment I proposed a conflict situation in which subjects would be punished for poor reaction-time performance, and that morphine would have different effects depending upon the extent of conflict and inferred anxiety. Abe listened, frowned. He then said something like, ‘that is a stupid idea’. Abe was blunt. About a week-and-a-half later he passed me in the hall, and stopped and said that we should talk a little bit about that experiment. He told me that after some thought it was a pretty good idea, but he did not think it would work out the way I had proposed it. Further discussions with Wikler and Hill led to a final experimental design. In that experiment we demonstrated that the effects of morphine would normally impair reaction-time; however, in a conflict, morphine would improve reaction-time (Hill et al. 1952b) Unfortunately, these early Lexington experiments, and many others performed prior to 1966 (e.g. Hill et al. 1952a,c), do not appear in current computer-based bibliographic search engines. A: Thus you got into behavioural psychopharmacology? CK: That is how I became involved in the field of behavioral pharmacology. We performed a whole series of experiments on the role of environmental factors on the effects of morphine, and these experiments continued after I left in 1952. The work for my dissertation, ‘The effects of anxiety and morphine on the perception of painful stimuli’ (Kornetsky 1954) was carried out at the hospital at Lexington, and the de facto director of my dissertation was Abe Wikler. The de jure director was James Calvin, Chairman of the Psychology Department at the University of Kentucky. TO NEW YORK AND WORK ON YOUNG HEROIN ADDICTS A: It was quite a stroke of luck to have the opportunity to work with those remarkable researchers in the early years of the field. Why did you leave the Addiction Research Center? CK: There were a number of factors, none because I was unhappy working in what was a fantastic research environment. The primary reason was the opportunity to continue with a juvenile drug addiction project that I was working on with Donald Gerard, a young psychiatrist doing his military service in the US Public Health Service Commissioned Corps. At the time it looked as if I would be called up for active duty in the Korean War. I was a second lieutenant in the Army Reserves. Harris Isbell was interested in keeping me on the staff, and because the Public Health Service was considered a military service and commissions could be transferred from one service to another, Isbell arranged for the transfer and a promotion. In June 1952, Don Gerard and I were transferred to duty in New York City to complete our study (Gerard & Kornetsky 1954, 1955a,b). The study was being carried out under the aegis of the National Institute on Mental Health, which was also part of the Public Health Service. A: How did that study get started? CK: The juvenile addiction study came about because there had been a dramatic increase in the number of heroin addicts under the age of 21 being admitted to the hospital at Lexington, which reflected an increase in heroin use in general by those under the age of 21. Don Gerard and I completed a study of a sample of 42 patients at the hospital. Then we realized that we needed a control population that could only be found in Chicago or New York. We opted for New York. What we looked for in New York were friends of heroin users who were never drug users and who lived in high-incidence areas of the city. We quickly found that there were hardly any urban youths in the age bracket we looked for who had never used heroin. We then settled for ‘not currently using’. We thought it would be easy to find a control group, but it took us a whole year to obtain 23 subjects that met our criteria. Although this was a reasonable control group, it was not perfect. Ideally we should have studied friends of our addict sample. We did the work in NY from July 1952 until June 1953. At the same time, NIMH gave a grant to Isidore Chein, in the Department of Social Relations at New York University, to do a study of juvenile drug addiction. This work led to one of the most comprehensive studies of juvenile use of heroin in New York City, The Road to H. (Chein et al. 1964) I always liked the first sentence of that book, ‘H is for Heaven, H is for hell, H is for Heroin. ‘What we looked for in New York were friends of heroin users who were never drug users. . .’ ‘We quickly found that there were hardly any urban youths in the age bracket we looked for who had never used heroin.’ A: Did you and Gerard work with Chein's group? CK: Only in the sense that we helped them get started. They were part of the NIMH extramural program of the period. Although they were competent social psychologists they knew little about drug addiction, and part of our role that year was to spend time with them at NYU in the planning of their study. At the completion of our study, Gerard stayed in New York and worked with Chein on the project. I was supposed to go into the intramural NIMH program at Bethesda. However, I received a call from Harris Isbell telling me about some LSD studies he was conducting, and that NIMH would loan me out for a year to work on LSD with Harold Abramson and Murray Jarvik at the Long Island Biological Laboratory at Cold Spring Harbor and Mt Sinai Hospital in New York. I worked with Murray at Mt Sinai, which gave me the opportunity to see the effects of LSD first-hand (e.g. Evans et al. 1956; Abramson et al. 1955). Working with Murray was the start of a friendship that has lasted ever since. WORK AT NIMH A: You seem to have been a participant in many of the earliest studies in the new era of psychopharmacology. What came next? CK: In September 1954 I moved to Bethesda, to the intramural program at NIMH, in the Laboratory of Clinical Science, in which Seymour Kety was the laboratory chief. I was given laboratory space, funding to hire a research assistant, and a ward full of non-psychiatric, young healthy volunteers willing to participate in experiments. At that time there were major changes beginning in the treatment of the mentally ill. Chlorpromazine had just been introduced and I decided I would compare the effect of this new ‘wonder’ drug with a variety of other centrally acting drugs, such as barbiturates and amphetamine, in normal volunteers and in schizophrenic patients (e.g. Kornetsky et al. 1957, 1959). A: Other contacts at this time? CK: At this time I became friendly with Allan Mirsky who was in the Laboratory of Psychology. Allan was using the Continuous Performance Test (CPT), a test of sustained attention, in the study of petit mal epilepsy. We decided that it would be useful to look at the effects of chlorpromazine on CPT performance in both schizophrenics and normal subjects (Mirsky & Kornetsky 1964; Kornetsky & Mirsky 1966). This was the start of our collaboration that continued for a number of years. A: Other contacts at this time? CK: It was at NIMH that I met Daniel X. Freedman. He was on sabbatical from Yale University and was studying some of the effects of LSD, sharing space in my laboratory. One day, I was watching Danny through a one-way screen doing psychotherapy with a schizophrenic patient when I suddenly had some insight in the schizophrenic process that made sense to me. The patient and Danny were engrossed in conversation when the patient seemed to be having auditory hallucinations about waterfalls. I was aware that a toilet had flushed, but Danny did not hear it because he was so focused on the patient. This suggested to me that maybe the schizophrenic was not able to filter irrelevant stimuli resulting in failure to focus attention. A: Your capacity for professional networking seems to have been highly productive. CK: I also met Joseph Cochin at NIMH. Joe was in the laboratory of Nathan Eddy and he was doing both animal and human studies of the analgesic effects of putative new analgesic compounds. Because I had written my dissertation on the analgesic effects of morphine, he and I immediately found some common interest. We not only became research colleagues but also close personal friends. We decided to study protracted tolerance to morphine. (Cochin & Kornetsky 1964). I continued these tolerance experiments when I moved to Boston University (Kornetsky & Bain 1968). BOSTON UNIVERSITY AND AN INTEREST IN SCHIZOPHRENIA A: Were you responsible for getting that interesting group of researchers to come to Boston University from NIMH? CK: Probably. They were, in the order of their coming to Boston University, Allan Mirsky, Joseph Cochin and Seymour Fisher. When Fisher came he brought with him Douglas McNair. I actually had met Seymour after I was at Boston University. He was working with Jonathan Cole at the NIMH Psychopharmacology Service Center and I was on the NIMH Psychopharmacology Review Committee. I had read some of his work and became excited about some of his ideas concerning the role of set and expectation in altering the response to drugs. They certainly supported some of the early experiments I carried out with Abraham Wikler and Harris Hill at the Addiction Center. I volunteered to help him set up an experiment to determine the effects of set and expectation on the effects of amphetamine. Roger Meyer also came to BU from NIMH. By that time I had switched my primary appointment from pharmacology to psychiatry and I had considerable influence on the research appointments that were being made. When I came to Boston University I decided that I wanted to continue my experiments in schizophrenia and to set up an animal laboratory. I was given space for human experimentation at Medfield State Hospital. Although I continued to perform animal experiments with opiates, my schizophrenia research continued well into the 1970s. These schizophrenia experiments, started when I was at NIH, confirmed that there was an attentional dysfunction in schizophrenia (e.g. Orzack & Kornetsky 1966). In many schizophrenic patients there is a trait deficit in attention that is reversed by chronic neuroleptics treatment (Wholberg & Kornetsky 1973). Because our findings suggested that a major aspect of the schizophrenic process was a problem in their inability to focus attention and my experiments at NIH with amphetamine suggested that at proper doses amphetamine would focus attention, I proposed in 1966 to give amphetamine chronically to schizophrenic patients with the expectation that it would have a therapeutic effect. I did not publish the results of this finding until 1976 when others were reporting that amphetamine exacerbated the schizophrenic symptoms (Kornetsky 1976). In most of the experiments reporting exacerbation of symptoms, the patients were more acute than the ones that I studied. That was the last paper I published on schizophrenia and for the most part the finding was ignored. Subsequently my research has focused on drug abuse. DRUG RESEARCH WITH A NEW FOCUS A: What was your new focus? CK: Much of the early thinking about drugs of abuse centered on the concept that the drug use was primarily a manifestation of some sort of psychopathology. People used drugs to normalize themselves. There was little attention given to the hedonic action of these abused substances, although at various times in the history of drug use there was the belief that the use of drugs was because of ‘moral weakness’, suggesting that there were hedonic effects. In the late 1960s, I was invited to a small meeting whose purpose was to determine the effects on the brain that abused substances might have that may be relevant to their use and continued use. I decided that an interesting area to review would be the brain reward system that was first described by Olds & Milner in 1954. I re-viewed the literature of drug effects on intracranial self-stimulation, or brain-stimulation reward, a term I prefer. I found that, with the exception of work by Larry Stein, no serious attempt to determine changes in the threshold caused by centrally active drugs had been done. Although increases in rate of response could be due to increased sensitivity of the animal to the stimulation, and decreases to a decrease in sensitivity, there was no way to determine if the effects might be due to actions of the drug on motor systems. Because I had been studying morphine analgesia in rats by intracerebral stimulation of a pain pathway, and using classic psychophysics to obtain a threshold, I thought I could apply this to brain-stimulation reward (Marcus & Kornetsky 1974). ‘Much of the early thinking about drugs of abuse centered on the concept that the drug use was primarily a manifestation of some sort of psychopathology.’ A: So the method you were developing was novel and very much your own? CK: I believe that my laboratory was the first that used the titration method for escape from intracranial aversive stimulation. All these titration experiments used a lever press as the operant response. However, in our single-dose experiments we wanted to use the animal only once. Training an animal to escape from foot shock or intracranial stimulation using a lever took approximately a week of daily training. In looking for a simpler manipulandum, Roger Kelleher, a colleague at Harvard, suggested that a wheel might better meet our needs. With the wheel we could train an animal in the morning and do our experiment in the afternoon. Also, we adopted the wheel manipulandum for our brain-stimulation reward experiments. A: You did some interesting work on cocaine at this time. CK: Yes. In examining the effects of cocaine on detection threshold we observed an interesting finding. At doses of cocaine that increase the sensitivity of the rat to rewarding brain stimulus, the animal becomes less sensitive to the detection of the stimulus (Kornetsky & Esposito 1981). This finding suggests that the hedonic effects of cocaine are achieved only at the possible loss of sensitivity to other stimuli in the environment. A: I sense that one of your core strengths was the sequentia l capacity to develop new laboratory procedures. CK: I have expanded the number of research procedures we use. For example, a number of years ago my laboratory began using drug self-administration in addition to brain-stimulation reward. One of the first questions that we addressed using the self-administration paradigm in the rat was an experiment to answer the question whether the combination of cocaine and heroin, the ‘speedball’, resulted in a synergistic effect, or the cocaine simply counteracted the depressant action of heroin. At doses of heroin that the rat would not self-administer, when combined with a low dose of cocaine, the self-administration rate of response of cocaine was potentiated (Duvauchelle et al. 1998) Another procedure that we adopted was the measurement of the local cerebral rate of glucose metabolism using the 2-deoxyglucose (2-DG) method of Sokoloff. These experiments indicated that the changes in the brain produced by cocaine, as measured by the 2-DG technique, were similar to those caused by rewarding brain stimulation. The major difference was the greater effect in motor areas after cocaine than after rewarding brain stimulation (Kornetsky et al. 1991). We used this technique later for the study of long-term effects of morphine and cocaine. A: How did you become interested in long-term effects? CK: My interest in long-term effects really started when I did the protracted studies on tolerance to morphine with Joe Cochin. It was rekindled in the 1980s. We found that in some way our experiments could permanently change the behaviour of an experimental rat. We decided to study the brains of these animal in the absence of drugs using the technique I had available, the 2-DG method for determining local cerebral rates of glucose metabolism. These experiments, I believed, were important, for not only did they show changes in cerebral glucose metabolism in these animals in the absence of morphine 2 weeks after the last sensitizing dose, but this effect was greatly enhanced if the environmental cues that were present during the morphine administration were present during the 2-deoxyglucose experiment (Kraus & Kornetsky 2000). We have similar results in basal 2-DG in animals that had previously been sensitized to cocaine (Knapp et al. 2002). CURRENT WORK A: Are you still studying opiate addiction? CK: Currently I am looking at one of the classic questions concerning whether there is an maturing-out process in the abuse of opiate drugs. We are presently just beginning to compare data on brain-stimulation reward, as well as the analgesic response between old and young rats, and it is too early to say that there are differences except to say that the brain reward system as measured by brain-stimulation reward is intact in the older rat. Also, experiments have been completed on sensitization to morphine and what is clear from these studies is that the aged rat sensitizes more readily and to a greater extent to morphine than the young rat. This difference is probably a function in the difference of the dopaminergic system between the young and old. Another new project is the developing of my brain-stimulation procedure in the mouse. The importance of this is that most of the experiments on genetic mutations are performed in mice. A: So you are still discovering new things, asking new questions. You have bee