21 



Mr. Waxman. You were not able to show there is physical de- 

 pendence. Am I correct that later studies did show a withdrawal 

 syndrome in rats on nicotine, meeting the third criteria for addic- 

 tion? 



Mr. DeNoble. That is correct. Those studies were not performed 

 in our laboratory. They have since been performed between 1984 

 and 1994. 



Mr. Waxman. Why did those studies reach a different result than 

 yours? 



Mr. DeNoble. I have reviewed those studies, and the conclusion 

 that I can come to is that those studies use very different measures 

 than what we were using, much more sensitive measures than we 

 were using. We modeled our dependence studies after work that I 

 had done with alcohol and with barbiturates. So we didn't fmd it 

 using those procedures, but other people have. 



Mr. Waxman. I'd like to ask you about your study on self-admin- 

 istration. Prior to your work, had anyone ever shown that rats will 

 self-administrate nicotine? 



Mr. DeNoble. There had been at least a half a dozen demonstra- 

 tions that rats will self-administrate nicotine. The problem with 

 most of those studies was that there was a confounding variable of 

 inducement. It was not clear. You couldn't interpret clearly wheth- 

 er nicotine was a true reinforcing agent, or whether it was coupled 

 to another thing going on in the animal's life. 



Mr. Waxman. So your studies succeeded where others failed. Can 

 you tell us why? 



Mr. DeNoble. I think the main difference between our study and 

 previous studies was the infusion time. Back in the 1970's and 

 1980's, it was common to infuse a drug solution into the vein of an 

 animal over a 13 to 15 second period. That's not what happens, if 

 you observe a smoker. 



A smoker takes smoke into his lung and nicotine is immediately 

 going to the lung, and immediately getting to the brain. So we basi- 

 cally shortened our infusion times to less than 4 seconds, so that 

 we were delivering a very quick, pulsed infusion. That seemed to 

 be the critical factor in our success. 



Mr. Waxman. I'd like to show you some posters, if we can have 

 those displayed? 



[Posters displayed.] 



Mr. Waxman. The first one. Exhibit 4, is entitled. Self-adminis- 

 tration Methodology. Could you explain it for us? 



[Exhibit No. 4 follows:] 



