addiction [46]. Ondansetron reduced the CPP induced by morphine in rodents, which is a measure of the use-reinforcing properties of a drug [47], and reduced place aversion, a measure of unpleasantness during naloxone-precipitated opioid withdrawal [48]. Ondansetron reduced naloxone-precipitated withdrawal behaviors in mice and rats in some [33,49,50] but not in all studies [48]. However, three analyses [51-53] of place conditioning and related models, found that 5-HT3-blocking agents were ineffective. In one of these studies, ondansetron was not effective at lower doses in rats, and was only variably effective at higher doses when the drug itself had an effect on place conditioning. In addition, this antagonist had no effect on heroin self-administration [54]. In humans, one-time low-dose oral ondansetron was not effective in reducing opioid cravings in addicts exposed to video materials containing drug-related cues [55]. On the basis of the results of the mouse genetic model, we designed a completely different type of clinical study in human volunteers. The results presented here represent the first indication that 5-HT3 antagonists can effectively ameliorate narcotic withdrawal symptoms in humans.
