17 



Mr. Waxman. Prior to your employment at Philip Morris, what 

 sort of scientific work had you done? 



Mr. DeNoble. I was working at the University of Minnesota, 

 under a sponsorship of the National Institute of Drug Abuse. My 

 work was with drug self-administration in non-human primates 

 and rodents. 



Mr. Waxman. You were doing animal tests on alcohol and bar- 

 biturates? 



Mr. DeNoble. That is correct, yes. 



Mr. Waxman. OK. You were previously doing work on drugs for 

 which there is a concern about both dependence and abuse? 



Mr. DeNoble. That's correct. 



Mr. Waxman. And at Philip Morris you did similar types of ani- 

 mal research on nicotine, is that correct? 



Mr. DeNoble. Very similar, yes. 



Mr. Waxman. Can you compare the tests you did on nicotine 

 with the tests that the National Institute on Drug Abuse would do 

 to determine if a drug has an abuse potential? 



Mr. DeNoble. Well, they are exactly the same tests. We did not 

 do drug comparisons, but the test models are exactly the same. 



Mr. Waxman. As I understand it, in order to test nicotine ana- 

 logues, you had to understand the brain effects of nicotine itself. 

 How did you approach this task? Where did you start? 



Mr. DeNoble. When the lab existed, we already had one test 

 which identified whether rats could tell us whether they were given 

 an injection of nicotine peripherally in the — systemically. Our first 

 model, to get to a direct effect of the pleasurable effects, if you will, 

 of nicotine, was to look at a self-administration model. That was 

 the primary screen. 



Mr. Waxman. I suppose that there are many brain effects that 

 a substance might have, and many tests that could be done. It is 

 my understanding that there are certain tests that qualify as hall- 

 marks of potential drug abuse or addiction. 



Am I correct that in the early 1980's, the three animal tests that 

 would be done to identify whether a substance was potentially ad- 

 dictive would be self-administration, tolerance, and physical with- 

 drawal? 



Mr. DeNoble. That is correct. 



Mr. Waxman. And isn't it true that you did all these tests and 

 that they were a central part of your work at the laboratory? 



Mr. DeNoble. That is also correct. 



Mr. Waxman. Now, would you briefly describe for us how you 

 tested for self-administration, tolerance, and physical dependence? 



Mr. DeNoble. Well, for self-administration, the animals were 

 surgically prepared with a catheter that lodged itself just above the 

 heart. The animals, after surgical recovery, could be hooked up to 

 an infusion pump. If the animal pressed one of two levers, one 

 lever didn't do anything, the other lever would deliver a nicotine 

 solution into the vein. 



If nicotine is a reinforcing agent, then the pressing of the lever 

 would increase, and that is what we found. We did several manipu- 

 lations and several investigations to clearly show that the animal 

 was pressing the lever to obtain nicotine. 



