The beginning, middle and end of my studies on conditioned taste aversions

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Darrell Edwards
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1 The highlight for July is by Dr. Ian Stolerman from the Institute of Psychiatry, King s College London. In this highlight, Dr. Stolerman describes his introduction to aversion learning and the context for his work since that introduction some 35 years ago. Coming from his research background in behavioral pharmacology and drug abuse, Dr. Stolerman has approached the issues of aversion learning and its implications in ways quite different from those studying basic toxicology (whose focus has been primarily on classic toxins and emetic agents). His initial work examined the effects of naloxone in opioid-dependent and opioid-naïve animals. As he notes, his group found that naloxone (even in naive animals) was able to induce aversions, suggestive that the blocking of endogenous tone of the opioid receptor by the opioid antagonist naloxone was aversive (a finding with implications beyond aversion learning per se in that it suggested an endogenous tone for reward mediated by the opioid receptor). Following his early work with naloxone, Dr. Stolerman examined the aversive effects of various drugs of abuse (e.g., nicotine, amphetamine) and raised the issue of the relative contribution of these aversive effects to their abuse potential (an issue that has resurfaced of late in discussions of drug abuse vulnerability and the possible role of the aversive effects of drugs as a protective factor). This work resulted in a seminal chapter entitled Oral self administration and the relevance of conditioned taste aversions (Stolerman and D Mello, 1981) in which aversion learning was nicely integrated with drug self administration (oral). This paper has provided the foundation for a variety of current investigations examining the interaction of the aversive and rewarding effects of drugs in determining drug acceptability. Dr. Stolerman s more recent work and focus has been on drug discrimination learning in which he has been both an active researcher and archivist. As he notes, his drug discrimination database ( was the incentive for our own with taste aversion learning and his research in this area extends his basic interest in behavioral pharmacology and drug abuse. Although Dr. Stolerman s primary research efforts are no longer in aversion learning, his questions about the nature of aversion learning predate much of the current controversy surrounding its motivational basis and his earlier work continues to drive much of the current work on aversion learning with drugs of abuse. The beginning, middle and end of my studies on conditioned taste aversions Ian Stolerman Section of Behavioural Pharmacology Institute of Psychiatry P049 De Crespigny Park London SE5 8AF i.stolerman@iop.kcl.ac.uk I probably began working on Conditioned Taste Aversions for the wrong reasons so here I tell the story of how it came about and why I have not published anything in the field for a few years. The story stretches back to the period of my doctoral research carried out in the 1960s at University College London. Apart from experiments required for my PhD thesis, I collaborated with Dr Ramesh ( Channi ) Kumar, another PhD student, in a long series of investigations on the oral intake of morphine and other substances. These studies were actually much more exciting than the work that I did for my PhD. It was pretty difficult to persuade rats to consume substantial amount of bitter morphine solutions when plain water was also available, but eventually we had some success which reinforced my interest in the drug dependence field. The work of a guy called Garcia showing how rats would learn to avoid solutions associated with illness-inducing events seemed vaguely related to what we were doing; however, we looked upon morphine as a positive reinforcer

2 and did not do any experiments specifically intended to address possible morphine-induced CTA. Then both Channi and I obtained our doctoral degrees and in January 1971 I left London for a three year postdoctoral stint with Murray Jarvik in the USA, first at Albert Einstein College of Medicine and then at UCLA. Contrastingly, Channi trained in psychiatry at the Institute of Psychiatry in London. During this era, reports of CTA produced by amphetamine and other abused drugs appeared, notably studies of Cappell and Le Blanc at the Addiction Research Foundation, Toronto 1. I was intrigued and much puzzled by the basis for such effects produced by stimuli that served as very effective positive reinforcers in operant conditioning procedures such as intravenous selfadministration. I was not in a position to work on the topic until I returned to England in But meanwhile, during my last year in the Jarvik laboratory, John Garcia was by happy coincidence appointed as a professor in the psychology department at UCLA. His presence was a tremendous stimulus that did much to reawaken my earlier interest in oral drug intake and CTA. I did not actually do any CTA work while in the department at UCLA, but I absorbed something of the ethos of the field that was tremendously exciting at the time because of the way that conditioning with long CS-US intervals appeared to contradict prevailing ideas. It seemed that to persuade the community to accept the notion, Garcia had to go through a process like that experienced by Galileo when according to legend he said of the planet earth and yet, it moves. Upon my return to England I took up a post in the pharmacology department of the University of Birmingham where I continued to enjoy considerable freedom in determining the direction of my research. Initially, while I was waiting for construction of my laboratory to be completed, I developed a collaboration with Charles Pilcher, a postdoctoral fellow in the psychology department, in which we developed a CTA procedure for assessing the aversive motivational strength of morphine withdrawal precipitated by the antagonist naloxone 2. The rats in these studies had twicedaily injections of morphine to establish a dependent state. I was pretty impressed and encouraged by the robust nature of these aversions. However, the sensitivity of the procedure was such that naloxone also produced very weak CTA in the control rats that did not have chronic twice-daily injections of morphine. This finding became apparent soon after the opioid pharmacologist Hans Kosterlitz visited Birmingham in 1975 and confided over a cup of tea that his group had identified an endogenous ligand for opioid receptors; indeed Hughes, Kosterlitz and colleagues published the discovery of the enkephalins just a few months later. Antagonism of endogenous opioid peptides could explain the weak aversions with naloxone in non-dependent rats. We went on to manipulate the procedure to enhance its sensitivity, and we were able to produce stronger CTA. Other evidence suggested this was a common property of the opioid antagonists available at the time and that it was indeed due to an action at opioid receptors rather than a non-specific artefact 3. The interpretation we placed upon the findings was simply that the endogenous tone of the opioid system helped to stabilise the balance between rewarding and aversive internal states or stimuli, and that by taking out the tonically rewarding opioid action the organism was shifted to a relatively aversive state that was the basis for the US in the CTA studies. This research area continued to develop further although conditioned place aversion methodology rather than CTA was used in many of the later studies. Around the same time I had the idea, in retrospect naïve and foolish, that CTA produced by typically positively reinforcing drugs could be converted to CTP (Condition Taste Preference) by manipulating features and parameters of the conditioning procedure. When construction of my laboratory in Birmingham was completed, I collaborated with David Booth and Charles Pilcher in studies where we tried to deconstruct CTA procedures, step by step, to determine what feature was responsible for the aversive drug property rather than for the positive reinforcement that we wanted to see manifested by CTP. David had a deep understanding of flavour preferences conditioned with nutrients, building on the work of Jacques Le Magnen in France. The idea was then to use the CTP as the behavioural endpoint in studies of drug action on brain reward systems, instead of the

3 technically more demanding self-administration procedure. Needless to say, this never happened, as summarised in a review 4. Try as we did, we were unable to produce CTP using amphetamine as a prototypical agent that was potent in both self-administration and CTA procedures. We manipulated both behavioural and pharmacological aspects of the CTA procedure and saw parametric variations in the intensity of CTA, but never anything that remotely approached a CTP! For example, when we introduced an operant response into the CTA procedure, we saw extremely powerful suppression of responding for an amphetamine-paired flavour; after just a single dipper presentation of the usually reinforcing saccharin solution, some of those rats showed immediate and total suppression of responding for the whole session. The anorexic effect of amphetamine was well known and in rats it markedly reduced the intake of food and water. Therefore we also tested the notion of conditioned hypodipsia as the basis for CTA, but results were negative 4. So in terms of the original objective of establishing a CTP procedure, the Birmingham experiments were a failure, although they did lead to a series of publications, and an invitation to spend a very stimulating sabbatical six months in the Department of Psychology of the University of Maryland, College Park. Thus, in 1980, I had the chance to discuss the implications of this and other work with colleagues at Maryland such as Jim Barrett, Lew Gollub and Bill Hodos. I think it was also around this time that I first met Tony Riley, during a short visit to the American University in Washington DC. Another enjoyable feature of the time in Maryland was its secondary function as an extended honeymoon (I was married shortly before the sabbatical began), but I also found time to write a review pulling together all the CTA experiments from Birmingham and discussing the relevance of CTA to the earlier work on oral drug self-administration 4. The article concluded with speculation that CTA might be considered homologous with the phenomenon of positive conditioned suppression, where a stimulus paired with behaviourally non-contingent presentation of a typical positive reinforcing stimulus could reduce the rate of an ongoing baseline of operant responding. This approach challenged the idea of CTA as really reflecting an aversive action of a drug. Bob Balster also raised the issue of the validity of CTA as a measure of drug avoidance at a seminar that I presented in 1980 at Virginia Commonwealth University. The concern was that there was no direct avoidance of, or escape from, the drug stimulus itself, and no evidence for learning of a new operant to prevent the presentation of the drug itself; there was just suppression of behaviour. After the sabbatical in Maryland, I returned to take up a position at the Institute of Psychiatry, University of London, where I stayed from 1980 to the present day. At the Institute I was reunited with former colleagues from the time of my doctoral studies, Channi Kumar and Malcolm Lader. My interest in nicotine and tobacco was reignited at this time and together with Channi I obtained a British Medical Research Council grant for studies on nicotine using two behavioural methods, operant drug discrimination (DD) and CTA. The idea was that DD indexed something close to the positive reinforcing properties of nicotine whereas CTA would be a metric for its aversive properties. Indeed, we were able to establish robust CTA with small doses of nicotine as the US, and we went on to examine various pharmacological manipulations in attempts to clarify its mechanism of action 5. We never succeeded in convincingly dissociating the mechanisms of nicotine-induced CTA from those of its DD effect, which was one of the reasons why I eventually abandoned its use. Nevertheless, we had been able to show that pharmacological antagonists could selectively block CTA induced by different drugs (nicotine and apomorphine); a nicotine antagonist blocked nicotine CTA while leaving apomorphine-induced CTA intact, and the pattern of results was precisely the opposite with a dopamine antagonist 6. This showed that pre-exposure effects in CTA studies could be pharmacologically specific which contrasted with the prevailing view at the time that almost any pre-exposure agent would block effects of any other drug as a US. At a later stage, we established a CTA procedure for mice, and used both CTA and the DD procedures to show greatly attenuated effects of nicotine in knockout mice that lacked nicotinic receptor subtypes that contained the beta2 subunit 7. I was also very gratified to see that Tony Riley s group and others were doing drug discrimination work related to our studies on the discrimination of drug mixtures 8.

4 The post in London also gave me the opportunity to establish the drug discrimination database. It began as a small venture to enable me to keep track of DD with nicotine and was expanded to cover all work in the DD area. It was first published in print form in 1982 and went through various mutations until it was made accessible on a web site in 1995, as a result of the ideas and dedicated efforts of Jonathan Kamien. Full details about this resource are available at It is interesting to note that in the early days of the DD database, my work on the project was stimulated by Tony Riley s CTA database 9 whereas subsequently it seems the DD database encouraged Tony to persist with his database and eventually develop the website through which it is now accessible and on which this article appears. In parallel with the studies of CTA, my group had continued work on DD and these studies expanded into projects on benzodiazepines and then on compound discriminative stimuli produced by administering mixtures of drugs; the relatively substantial progress made in my DD work became a factor in the decision to suspend the CTA studies. Other factors in this decision were the shift in my group s work to studying the effects of nicotine in an operant paradigm for assessing attentional behaviour and the continuing uncertainty about the interpretation of CTA effects in terms of motivational properties of the US. This uncertainty was magnified by Sue Grigson s argument to the effect that CTA reflected the positive rewarding effects of drugs rather than their aversive properties. Although this remains as a controversial position, it did rather discourage my use of CTA as a measure for aversive properties. It is hard to defend the use of the technique for that purpose in grant applications when other authors argue for a precisely opposite interpretation! Similarly, in order to obtain ethical approval for use of animals, it has become increasingly important to be able to argue convincingly for the validity of an animal procedure as a model for a well specified drug effect in humans. Perhaps we need studies of the putative aversive properties of amphetamine, morphine and other addictive substances using operant conditioning procedures. Here I am thinking of (1) tests for the ability of response-contingent drug infusions to suppress operant behaviour maintained by a conventional reinforcer - punishment paradigms - and (2) tests of the ability of response-contingent termination of an experimenter-programmed infusion of drug to maintain an operant - negative reinforcement paradigm. Interestingly, nicotine has been shown to have strong punishing and negative reinforcing effects in these paradigms, but little work of that type has been reported with the classical self-administered drugs such as the typical psychomotor stimulants and the opioids. In conclusion, much remains to be done to determine the nature of CTA in relation to other effects of abused substances; such work may help to shape its role in future behavioural pharmacology research. References 1. Cappell H, LeBlanc AE (1971) Conditioned aversion to saccharin by single administrations of mescaline and d-amphetamine. Psychopharmacologia 22: Pilcher CWT, Stolerman IP (1976) Conditioned flavor aversions for assessing precipitated morphine abstinence in rats. Pharmacology Biochemistry and Behavior 4: Stolerman IP, Pilcher CW, D'Mello GD (1978) Stereospecific aversive property of narcotic antagonists in morphine-free rats. Life Sciences 22: Stolerman IP, D'Mello GD (1981) Oral self-administration and the relevance of conditioned taste aversions. In: Thompson T, Dews PB, McKim WA (eds) Advances in Behavioural Pharmacology volume 3. Academic Press, New York, pp

5 5. Pratt JA, Stolerman IP (1984) Pharmacologically specific pretreatment effects on apomorphinemediated conditioned taste aversions in rats. Pharmacology Biochemistry and Behavior 20: Kumar R, Pratt JA, Stolerman IP (1983) Characteristics of conditioned taste aversion produced by nicotine in rats. British Journal of Pharmacology 79: Shoaib M, Gommans J, Morley A, Stolerman IP, Grailhe R, Changeux J-P (2002) The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology 42: Hutchinson AC, Riley AL (1997 ) The discriminative stimulus effects of a cocaine-alcohol mixture. In: Harris LS (ed) Problems of Drug Dependence NIDA Research Monograph 174. U.S. Department of Health and Human Services, Rockville, Maryland, pp Riley AL, Clarke CM (1977) Conditioned taste aversions: a bibliography. In: Learning mechanisms in food selection. Barker L, Best M, Domjan M (eds) Baylor University Press.

DAVID N. KEARNS, PH.D.

DAVID N. KEARNS, PH.D. Psychology Department American University Washington, DC 20016 Phone: 202-885-1725 Email: kearns@american.edu EDUCATION 2005 American University Washington, DC Ph.D., Psychology