Computational haplotype-based genetic analysis indicated that genetic variation within the Htr3a gene could affect interstrain differences in the degree of physical dependence developing after chronic morphine exposure. This computational prediction was confirmed in pharmacological experiments; a 5-HT3 receptor antagonist reduced two distinct manifestations of opioid withdrawal in mice. Similarly, the CPP paradigm commonly used to estimate the addictive properties of drugs showed that blockade of the 5-HT3 receptor completely abolished the reinforcing properties of morphine. Furthermore, Htr3a mRNA expression within three brainstem nuclei associated with opioid dependence was strongly down-regulated after chronic morphine exposure. Alterations in brainstem 5-HT3 protein followed the same pattern. The strain-dependent and brain-region-specific differences in Htr3a mRNA and 5-HT3 protein expression within the CNS provide a potential mechanism that could partially explain how genetic differences within Htr3a affect susceptibility to opioid dependence. On the basis of these results, a widely used antiemetic drug (ondansetron) was tested in human volunteers, and these 5-HT3 receptor antagonists were shown to significantly reduce the objective signs of morphine withdrawal in humans. Therefore, this report provides the first demonstration that a 5-HT3 antagonist, which is a readily available medication, can reduce the severity of narcotic drug withdrawal symptoms in humans.
