and then as an associate senior scientist, a position I was promoted to in 1983. During that time, I established and directed a behavioral pharmacology laboratory to study the behavioral and physiological effects of nicotine in rats. Our goal was to identify the effects of nicotine in the central nervous system, and to establish structure activity relationships among organically synthesized analogues of nicotine. The purpose of this nicotine analogue program was to develop an analogue that would retain the physiological effects of nicotine in the brain as well as the behavioral effects, but not have adverse effects on the cardiovascular system. Our program was successful in identifying a series of compounds which met this criteria. In order to behaviorally evaluate nicotine analogues, a characterization of the behavioral effects of nicotine in rats using a variety of offered conditioning procedures needed to be developed. One of the earliest test procedures we used was a nicotine self-administration test. In this procedure, an animal can press a lever and deliver a drug solution into its vein. If the solution has reinforcing properties or qualities, the animal will continue to press the lever. We found that nicotine functioned as an intravenously delivered reinforcer in rats in the absence of any inducement conditions. In previous studies, inducement conditions made the analysis of nicotine's reinforcing effects difficult to assess. Our result demonstrated for the first time that nicotine shared common characteristics with other drugs that are delivered intravenously. In other studies, we also found that rats would develop tolerance to repeated injections of nicotine, and this tolerance was in part behavioral and in part physiological. Following tolerance development, higher doses of nicotine were required to produce the effects that were both quantitatively and qualitatively similar to before tolerance development. We also examined the potential of nicotine to produce a physical dependence in rats. In two separate experiments, we were not able to show that nicotine produced a withdrawal syndrome. There were several other studies performed in the laboratory with nicotine. And although none of these very few of these studies were published, almost all of this research has since been replicated, confirmed by other investigators around the world. In 1982, however, we began to investigate the behavioral effects of another smoke component. To the best of my knowledge, this research has never been replicated and therefore awaits scientific confirmation. In our search to identify molecules in cigarette smoke that may have reinforcing properties other than nicotine, we identified a molecule called acetaldehyde. It was in high concentrations in cigarette smoke. Because acetaldehyde could be delivered to the brain in seconds, and is highly reactive with catecholamines, we hypothesized that, one, acetaldehyde functions as a reinforcer for rats; and, two, that possibly interactions with nicotine could be achieved. Our research confirmed that acetaldehyde was a reinforcer for rats, and the reinforcing properties of acetaldehyde and nicotine combinations would interact producing additive effects in these animals. I would like to state that senior research management in Richmond, Va., as well as top officials of the Philip Morris Company in New York, continually reviewed our research and approved our research. Senior management also reviewed and made final decisions determining whether data could be published, presented at scientific meetings, or even discussed in the scientific community. With regard to the Philip Morris press release, dated March 31st, 1994, the statements made concerning my research and my assessment of the self-administration experiments are out of context and misleading. Further, during my employment with Philip Morris, three manuscripts were approved for publication. Two of these manuscripts were subsequently ordered to be withdrawn by the company after this approval. In addition, a 1983 scheduled presentation of the nicotine self-administration paper at the American Psychological Association meeting was also blocked by the company. Finally, without prior discussion or prior warning, the behavioral pharmacology laboratory was abruptly closed in April of 1984. Mr. Chairman, and members of the committee, I would like to thank you for reading our statement, and I welcome any questions. [The prepared statement of Dr. DeNoble follows:] STATEMENT OF VICTOR JOHN DENOBLE Mr. Chairman and members of the committee, I am Dr. Victor John DeNoble, a behavioral psychologist, and I am senior behavior analyst for the Community Mental Retardation Program for the State of Delaware. I am grateful to have this opportunity to discuss my research at this hearing on tobacco. From 1980 to 1984, I was employed at the Philip Morris Research Center in Richmond, Virginia as an associate senior scientist. My responsibilities were to establish and direct a behavioral pharmacology laboratory to study the behavioral and physiological effects of nicotine and other smoke components in rats. Our initial goal was to identify the behavioral effects of nicotine on the central nervous system and to establish structure activity relationships among organically synthesized nicotine analogues. The purpose of the nicotine analogue program was to develop an analogue that would retain physiological and behavioral effects in the brain and be devoid of any pharmacological effects in other organs, specifically, the cardiovascular system. In order to accomplish this goal, a characterization of the behavioral effects of nicotine in rats using a variety of operant conditioning procedures needed to be developed. With regard to the nicotine analogue program, our primary behavioral test was a nicotine drug discrimination procedure. Rats were trained to identify whether they had been injected with nicotine or saline. Using nicotinic-cholinergic antagonists, we demonstrated that the rats ability to discriminate (identify) whether it was injected with nicotine or saline was mediated by nicotine's effect in the brain not by nicotine's effect on the peripheral nicotinic receptors. This test procedure was used to identify nicotine analogues that would mimic the effects of nicotine in this discrimination procedure. This behavioral data was then combined with nicotinic receptor binding data, as well as peripheral pharmacology data generated outside Philip Morris Research Center to develop structure-activity relationships among these analogues. The goal of this program was to identity a nicotine analogue that would have central nervous system effects without effects on the cardiovascular system. In our self-administration studies we demonstrated that: (1) nicotine functioned as an intravenously delivered reinforcer for rats; (2) that rats would press levers several times for a single injection; (3) that nicotine self-administration was controlled, at least in part, by nicotine levels in blood or tissue; (4) that the reinforcing effects were mediated by central nicotinic-cholinergic receptors; (5) that endogenous opioid receptors did not mediate nicotine's reinforcing effects and, finally; (6) that termination of chronic self-administration of nicotine over several weeks did not result in observable behavioral signs of a physiological dependence. With regard to this last observation, we extended our findings by examining the effects of nicotine self-administration on concurrent lever pressing maintained by food. Concurrent nicotine self-administration was shown not to interfere with lever pressing for food and that discontinuing access to nicotine self-administration did not alter the rate or pattern of food intake. In a related experiment, we examined the effects of pharmacological antagonism of chronic nicotine administration on lever pressing maintained by food. The results showed that antagonism of chronically administered nicotine also did not result in a disruption of schedule-controlled behavior. Termination or antagonism of chronic nicotine administration did not result in a disruption of lever pressing for food suggesting that chronic administration of nicotine did not result in a physiological dependence in these tests. Studies on the development and loss of tolerance to chronic nicotine exposure revealed that tolerance to the behavioral effects of nicotine developed following chronic administration of nicotine. The study design allowed us to demonstrate that both physiological and behavioral tolerance develops to chronic nicotine administration. Following tolerance development, higher doses of nicotine were required to produce effects that were both quantitatively and qualitatively similar to those observed before tolerance had developed. Our laboratory also conducted a series of studies on the behavioral effects of nicotine when injected directly into the ventricles of the brain, as well as, when nicotine is injected into different brain sites. This research was directed at identifying the neuroanatomical substrates mediating the behavioral effects of nicotine. These test procedures also became a primary screening tool for the nicotine analogue program since the behavioral effects of nicotine were shown to be controlled by nicotine's effect on the brain, not on peripheral systems. The above mentioned studies summarizes major research efforts with nicotine and nicotine analogues. There were several other experiments which provided support for these major research programs. Almost all of the research that occurred between 1980 and 1984 has subsequently been replicated, confirmed and extended by other investigators around the world. However, in 1982 we began to investigate the behavioral effects of another smoke component. To the best of my knowledge, this research has never been replicated, and therefore, awaits scientific confimation. In our search to identity other molecules in tobacco smoke that may have reinforcing properties, we identified acetaldehyde as a major component of gas phase smoke. Tobacco itself does not contain acetaldehyde, but, as a product of pyrolysis, large amounts of acetaldehyde are formed and delivered in the gas phase of smoking. Interest in this molecule began in the mid-1960's when it was demonstrated that another aidehyde, formaldehyde, was shown to condense with endogenous catecholamines to form compounds called tetrahydroisoquinolines (TIQ's). In the mid 1970's, it was demonstrated that acetaldehyde, a major metabolite of alcohol could also form TIQ's. TIQ's have been hypothesized to act as "false neurotransmitters" in catecholamine-containing neurons, The fact that acetaldehyde is in high concentration in smoke, is delivered to the brain in seconds, and is highly reactive with catecholamines led us to hypothesize that: (1) acetaldehyde may function as an intravenously delivered reinforcer for rats; (2) that the reinforcing effect would be mediated by the formation of TIQ's; and that, (3) interactions with nicotine's reinforcing effects would be possible. Our research confirmed that acetaldehyde was: (1) a reinforcer when delivered intravenously; (2) that rats would press levers several times for a single injection; and (3) that termination of acetaldehyde access did not result in observable signs of a physiological dependence. In a related series of experiments, we further demonstrated that the reinforcing properties of nicotine and acetaldehyde would interact behaviorally producing additive effects in rats. These results formed the basis for the hypothesis that both nicotine and acetaldehyde are reinforcing agents in cigarette smoke and that their interaction would result in an enhanced reinforcing effect in humans. I would like to thank you for allowing me to place my statement in the record. Mr. WAXMAN. Thank you very much, Dr. DeNoble. If the members have no objection, we're going to recognize each one in turn for 10 minutes, but since these are our only witnesses for today, if someone is pursuing a line of questioning that might go a little beyond the 10 minutes, I hope we'll be willing to extend the courtesy to continue that line of questioning. Dr. DeNoble, I want the clerk to give you Exhibit 1, which is your resume. And I note that you've published more than 20 articles, and that you have held teaching positions at 7 universities. [The document follows:] Response Acceleration and Suppression Produced by Response-Independent Food National_Institiute of Drug University of Minnesota, Department of Current Position: Senior Behavior Analyst, Department of Mental Retardation, Delaware State Mental RESEARCH EXPERIENCE: Manager, Development and Training, R&D Operations, Du Pont Research Associate, Central Nervous System Research, The DuPont Research Associate, Central Nervous System Research, E. I. Research Associate, CNS Research, Ayerst Laboratories Research, Associate Senior Scientist, Project Leader, Behavioral Project Leader, Behavioral Pharmacology Laboratory, Philip RESEARCH EXPERIENCE (cont'd): Research Associate, Psychiatry Research Unit, University of Research Associate, Department of Biopsychology and Anatomy, Senior Research Scientist, Electrophysiology Laboratory, TEACHING EXPERIENCE: 1989 · 1990 Adjunct Associate Professor, Department of Psychology, Adjunct Assistant Professor, Department of Psychology, Trenton Adjunct Associate Professor, Department of Psychology, Virginia Adjunct Associate Professor, Department of Psychology, State Adjunct Assistant Professor, Department of Psychology, City Adjunct Lecturer, Department of Psychology. City University of Adjunct Lecturer at State University of New York, Farmingdale. Adjunct Lecturer at Adelphi University. GUEST REVIEWER FOR: Neuropsychopharmacology Science Pharmacology Biochemistry and Behavior Physiological Psychology Physiology and Behavior Life Sciences 1984 Division 28 - American Psychological Association 1985 Division 28 - American Psychological Association |