In order to provide information about the hypothesis that endogenous opioids mediate the reinforcing properties of cigarette smoking, the present study examined the effects of naloxone, an opioid antagonist, on cigarette smoking in seven normal volunteers. The study used experimental procedures that had previously been shown sensitive for detecting the effects of other drugs, (including a nicotine antagonist) on smoking. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Sixty minutes before each 2 h smoking session subjects received an IM injection of naloxone HCl (0.0625, 0.25, 1.0, or 4.0 mg/kg) or placebo. Each subject received each treatment three times in a mixed order across days. Naloxone did not significantly affect any measure of cigarette smoking including number of cigarettes, number of puffs, or expired air carbon monoxide level. Naloxone did, however, produce significant dose-related increases in subject ratings of yawning, stretching, and relaxation. The results of the present study provide no support for the endogenous opioid theory of smoking reinforcement.

Second-order schedules of drug self-administration were developed to incorporate the effects of drug-related environmental stimuli into an animal model of drug abuse, making it more similar to human situations. Ironically, little is known about how human subjects behave under these schedules. In this study, human volunteers with a history of cocaine use worked on a second-order schedule in which every 100th lever response produced an auditory-visual brief stimulus (2 s). The first stimulus produced after 1 h was extended to 10 s and paired with an intravenous injection of cocaine (25 mg). Up to three injections were allowed per session. In different phases of the experiment, presentation of the brief stimulus was discontinued and/or saline solution (placebo) was injected instead of cocaine. Injections of cocaine were found to maintain responding even when the brief stimulus was not presented. Placebo injections alone did not maintain responding. In contrast, the brief stimulus maintained high levels of responding under placebo conditions, even though selfreports indicated that subjects could clearly discriminate that they were not receiving cocaine. These results demonstrate that drugrelated environmental stimuli can maintain persistent drug seeking during periods of drug unavailability. As this procedure directly measures the effects of stimuli on drug seeking, it may provide a valuable complement to indirect measures, such as self-reports of craving, that are often used with human subjects. The similarity of the response patterns in humans and animals also supports the use of second-order schedules in animals as a valid model of human drug seeking.

The effects of nicotine-containing chewing gum on cigarette smoking and subjective and physiological response were evaluated in eight normal volunteers. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Before 90-min smoking sessions subjects chewed two pieces of placebo or nicotine-containing gum (0, 2, 4, or 8 mg) under double-blind conditions. Each subject received each treatment four times in a mixed order across days. Analysis of the chewed gum for remaining nicotine revealed that the mean delivered nicotine doses were 0, 1.02, 2.39, and 5.20 mg nicotine. Nicotine preloading produced dose-related increases in plasma nicotine, while producing dose-related decreases in various measures of cigarette smoking including number of cigarettes smoked, number of puffs taken, expired air carbon monoxide level, and ratings of smoking satisfaction. Nicotine preloading produced dose-related increases in ratings of gum dose-strength, while producing decreases in ratings of gum dose acceptability and liking. Heart rate and blood pressure were not significantly affected by nicotine gum. Taken together, the present results confirm that responses to nicotine in the gum preparation are orderly and related to dose, and the results suggest that the efficacy of treating tobacco dependence with nicotine gum may be enhanced by increasing the administered dose.