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Mr. Kreidler. I find the first sentence of the memo particularly 

 interesting. It states, "Nicotine is a powerful pharmacological agent 

 with multiple sites of action and may be the most important com- 

 ponent in cigarette smoke." This certainly paints a different picture 

 of nicotine than the picture painted by the tobacco company execu- 

 tives 2 weeks ago. Do you have a response to that? 



Mr. DeNoble. This statement, that it is a powerful pharma- 

 cological agent, justified much of the research at the research cen- 

 ter, I mean, the whole thrust of research of this program was work 

 on nicotine not as a flavorant but as a pharmacological agent. 



It was our belief back then and my belief today that nicotine is 

 an agent in cigarette smoke that is reinforcing, and it is a contribu- 

 tor to why people smoke. That was the premise of our whole pro- 

 gram. 



Mr. Kreidler. Now I would like to show Exhibits 19, 20, and 21, 

 which are the pictures of rats in the analogue program. 



Mr. Kreidler. Doctor, would you please tell us what we're seeing 

 in these pictures here? 



Mr. DeNoble. The poster on, I guess, my right, is a picture of 

 an animal who has been anesthetized. And we are placing a 

 canula, basically a needle, into different areas of its brain. 



The work that came out of Leo Abood's lab in Rochester indicated 

 that if you placed nicotine directly in the brain, that the animal 

 would have a particular behavioral response. And he went on to 

 show, very elegantly, that effect was only produced with nicotine- 

 like drugs. 



So we went back to our lab, cannulated animals to see if we 

 could replicate and extend his findings and use it as a tool. The 

 center picture is an animal who is reaching up to grab a pellet of 

 food. He's got a brain canula, and we injected 5 microliters of nico- 

 tine into his brain, and that's the same animal in the last photo- 

 graph. 



You can see he is not responding to the food pellet. That syn- 

 drome was called prostration syndrome. It was unique to nicotine. 

 The animal becomes splayed, he becomes unresponsive for about 12 

 minutes. We went on to characterize that behaviorally, to show 

 pharmacologically that it was an effect of nicotine on brain recep- 

 tors. And that was a primary screening tool in our laboratory in 

 the nicotine analogue program. 



Mr. Kreidler. Did you succeed in developing a nicotine analogue 

 that would have the effects that nicotine has on the brain but does 

 not have nicotine's effect on the heart? 



Mr. DeNoble. We did identify a series of analogues that met our 

 minimal criteria for that effect, yes. 



Mr. Kreidler. Did Philip Morris ever use the analogues, to the 

 best of your knowledge? 



Mr. DeNoble. No, sir. I have no knowledge of that. 



Mr. Kreidler. Do you know why not? 



Mr. DeNoble. No. We had several discussions about what we 

 would do with it when we found it. And once we found it, nothing 

 was done with it. The indications to us were that we'll take a wait- 

 and-see attitude. 



Quite honestly, I think that scientifically that was an interesting 

 finding. It could be conceived of as a major breakthrough, in my 



