Lack of evidence for context-dependent cocaine-induced sensitization in humans: Preliminary studies

Cocaine-induced behavioral sensitization is the well-documented phenomenon where repeated doses of cocaine elicit increasingly greater effects on motoric activity in rats. Some observations suggest that behavioral sensitization may provide a model for understanding the mechanisms of drug-craving elicited by environmental triggers or cues. The process of fully validating such an animal model for its ability to detect effective anticraving medicines is a difficult and long-term undertaking. As a first step in that direction, we decided to determine if cocaine can produce conditioned behavioral sensitization in humans using a paradigm fairly similar to that used for rodents. Because humans do not react to cocaine with the pronounced motor activation observed in rodents, we measured a variety of end points, including blood pressure (BP), heart rate (HR), respiratory rate, pupil diameter, hormones (prolactin and cortisol), and subjective responses using the questionnaire for drug-related feelings (QDRF) and the EEG. To mimic the home and test cages used in rodent studies, two rooms were used: a small test chamber and a regular room with a window and furnishings. On day 1 each subject received a drug infusion (either saline or 40 mg cocaine IV) in both locations. On day 2, all subjects received an infusion (saline or 25 mg cocaine IV) in the test chamber. All drug infusions were conducted double blind. The paired group received cocaine on both days in the test chamber. The unpaired group received cocaine in regular room on day 1, and cocaine in the test chamber on day 2. A control-1 group received saline at both locations on day 1, and cocaine on day 2 in the test chamber. A control-2 group [4] received cocaine in the test chamber on day 1 and saline in the test chamber on day 2. Conditioned-sensitization was not observed. However, conditioned tolerance was observed for cocaine-induced changes in plasma prolactin levels and diastolic blood pressure. Because rodent studies use cocaine-naive subjects and this study used cocaine-experienced subjects, these data suggest that prior experience with cocaine may alter it ability to poduce sensitization. Viewed collectively, the present investigation suggests caution in the design of both human and animal studies.