6> 



and then as an associate senior scientist, a position I was promoted 

 to in 1983. During that time, I established and directed a behav- 

 ioral pharmacology laboratory to study the behavioral and physio- 

 logical 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 character- 

 ization 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-administra- 

 tion test. In this procedure, an animal can press a lever and deliver 

 a drug solution into its vein. If the solution has reinforcing prop- 

 erties 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 nico- 

 tine'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 be- 

 havioral and in part physiological. Following tolerance develop- 

 ment, 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 stud- 

 ies were published, almost all of this research has since been rep- 

 licated, 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 re- 

 search 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 identi- 

 fied 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 rein- 

 forcing properties of acetaldehyde and nicotine combinations would 

 interact producing additive effects in these animals. 



I would like to state that senior research management in Rich- 

 mond, Va., as well as top officials of the Philip Morris Company in 



