Rapid acute tolerance and opponent process-like effects in response to the hedonic effects of cocaine have been reported in human studies of smoked coca paste (Van Dyke and Byck, 1982) (Figure 1A). After a single smoking session, the onset and intensity of the “high” are very rapid via the smoked route of administration, and a rapid tolerance is manifest. The “high” decreases rapidly despite significant blood levels of cocaine. Even more intriguing is that human subjects also actually report a subsequent “dysphoria,” again despite high blood levels of cocaine. Intravenous cocaine produced similar patterns of a rapid “rush” followed by an increased “low” in human laboratory studies (Breiter et al., 1997) (Figure 1B). With intravenous cocaine self-administration in animal models, such elevations in reward threshold begin rapidly and can be observed within a single session of self-administration (Kenny et al., 2003) (Figure 2), bearing a striking resemblance to human subjective reports. These results demonstrate that the elevation in brain reward thresholds following prolonged access to cocaine failed to return to baseline levels between repeated, prolonged exposure to cocaine self-administration (i.e.,
