From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics

Abstract

Objectives 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. Conclusion These studies show the power of in-silico genetic mapping, and reveal a novel target for treating an important component of opioid addiction.

Availability of dopamine and serotonin transporters in opioid-dependent users—a two-isotope SPECT study

“…Although the addictive properties of opiates are generally considered to be mediated by an increased release of dopamine in the striatum, recent pharmacological and genetic experiments also indicate involvement of the 5HT system in the behavioral and reward responses to opiates (Chu et al 2009;Tassin 2008;Weitemier and Murphy 2009;Zhao et al 2007). In this study, it was found SERT availability tended to be lower in the opioid users during methadone treatment than in the controls.…”

Genetic Susceptibility to the Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Is MHC Dependent

“…In fact, analysis of mouse genetic models has generated novel approaches for treatment of narcotic drug addiction (20) and for prevention of acetaminophen-induced liver toxicity (21). Differences in response to RSV have been observed among inbred mouse strains, including differences in viral load (22)(23)(24) postinfection, and in eosinophilic responses after vaccination with the RSV glycoprotein (25,26).…”

Effect of Full-Dose Ondansetron on Tobacco Use among Male Alcohol- Dependent Outpatients - A Preliminary Study

“…In addition, other studies on ondansetron efficacy in treating depressive and anxiety symptoms (concomitant to or even derived from other illnesses) have successfully tested doses between 8 and 24 mg daily, reporting a reduction in depressive symptoms [21,34], decrease of anxiety in subjects with Obsessive Compulsive Disorder [35], and even improvement on cognitive impairments among schizophrenics [36]. Also, 8 mg ondansetron (but not 4 mg) was shown to be useful for decreasing opiate withdrawal signs [37].…”