This report summarizes a number of experiments designed to examine the changes in the threshold for intracranial self-stimulation (ICSS) in the rat after the administration of morphine and a number of narcotic agonist-antagonists, as well as three nonnarcotic drugs that have extensive nonmedical use (cocaine, d-amphetamine, and phencyclidine). The results of these experiments clearly indicate that morphine lowers the threshold for ICSS and, furthermore, there appears to be little or no tolerance to this effect. The only mixed agonist-antagonist that consistently lowered the ICSS threshold was pentazocine. Cocaine, d-amphetamine, and to a lesser degree, phencyclidine also lowered the ICSS threshold. These results suggest that the abuse liability of these agents may be directly related to their ability to sensitize the neural substrate involved with natural reward.