Previous studies have suggested a role for corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) in the aversive and anxiogenic effects of withdrawal from opiates and ethanol. To test whether this role of CRF extends to cocaine withdrawal as well, the release of CRF in rat amygdala was monitored by intracranial microdialysis during a 12-hour session of intravenous cocaine self-administration and subsequent 12-hour cocaine withdrawal period. Cocaine self-administration tended to lower dialysate CRF concentrations to approximately 75% of CRF levels in controls. In contrast, subsequent cocaine withdrawal produced a profound increase in CRF release, which reached peak levels of approximately 400% of baseline between 11 and 12 hours post-cocaine. These results provide evidence that cocaine withdrawal activates CRF neurons in the amygdala, a site that has been implicated in emotional and anxiogenic effects of stress and drug withdrawal syndromes.