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 chron- 

 ically 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 nico- 

 tine ciid not result in a physiological dependence in these tests. 



Studies on the development and loss of tolerance to chronic nicotine exposure re- 

 vealed 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 be- 

 fore tolerance had developed. 



Our laboratory also conducted a series of studies on the behavioral effects of nico- 

 tine when injected directly into the ventricles of the brain, as well as, when nicotine 

 is injected into different Drain 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 ef- 

 fect 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 conflmation. 



In our search to identity other molecules in tobacco smoke that may have reinforc- 

 ing 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. In- 

 terest in this molecule began in the mid-1960's when it was demonstrated that an- 

 other aldehyde, 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 func- 

 tion 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 nico- 

 tine's reinforcing effects would be possible. 



Our research confirmed that acetaldehyde was: (1) a reinforcer when delivered in- 

 travenously; (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 dem- 

 onstrated that the reinforcing properties of nicotine ana acetaldehyde would interact 

 behaviorally producing additive effects in rats. 



These results formed the basis for the hypothesis that both nicotine and acetal- 

 dehyde 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 mem- 

 bers 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 cour- 

 tesy 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 arti- 

 cles, and that you have held teaching positions at 7 universities. 



[The document follows:] 



