title: From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics.
abstract: OBJECTIVE
  Addiction to opioid narcotics represents a major public health challenge. Animal models of one component of addiction, physical dependence, show this trait to be highly heritable. The analysis of opioid dependence using contemporary in-silico techniques offers an approach to discover novel treatments for dependence and addiction.
  
  
  METHODS
  In these experiments, opioid withdrawal behavior in 18 inbred strains of mice was assessed. Mice were treated for 4 days with escalating doses of morphine before the administration of naloxone allowing the quantification of opioid dependence. After haplotypic analysis, experiments were designed to evaluate the top gene candidate as a modulator of physical dependence. Behavioral studies as well as measurements of gene expression on the mRNA and protein levels were completed. Finally, a human model of opioid dependence was used to quantify the effects of the 5-HT3 antagonist ondansetron on signs and symptoms of withdrawal.
  
  
  RESULTS
  The Htr3a gene corresponding to the 5-HT3 receptor emerged as the leading candidate. Pharmacological studies using the selective 5-HT3 antagonist ondansetron supported the link in mice. Morphine strongly regulated the expression of the Htr3a gene in various central nervous system regions including the amygdala, dorsal raphe, and periaqueductal gray nuclei, which have been linked to opioid dependence in previous studies. Using an acute morphine administration model, the role of 5-HT3 in controlling the objective signs of withdrawal in humans was confirmed.
  
  
  CONCLUSIONS
  These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction.
authors.affiliation: Department of Anesthesiology, Stanford University, Palo Alto, California, USA.
authors.forename: Larry F
authors.initials: LF
authors.lastname: Chu
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.forename: Xiangqi
authors.initials: X
authors.lastname: Li
authors.forename: Peyman
authors.initials: P
authors.lastname: Sahbaie
authors.forename: Nicole
authors.initials: N
authors.lastname: D'arcy
authors.forename: Guochun
authors.initials: G
authors.lastname: Liao
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
authors.forename: J
authors.initials: J
authors.lastname: David Clark
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects; D019295:Computational Biology; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics* / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D019966:Substance-Related Disorders / Q000235:genetics*
chemical_list: D000701:Analgesics, Opioid; D009294:Narcotics; D012333:RNA, Messenger; D044406:Receptors, Serotonin, 5-HT3; D009020:Morphine