title: Role of the serotonergic system in reduced pulmonary function after exposure to methamphetamine.
abstract: Although use of methamphetamine (MA) by smoking is the fastest growing method of administration, very limited data are available describing the effects of smoked MA. Using a murine inhalation exposure system, we explored the pulmonary effects of low-dose acute inhalation exposure to MA vapor (smoke). Inhalation of MA vapor resulted in transiently reduced pulmonary function, as measured by transpulmonary resistance, dynamic compliance, and whole-body plethysmography compared with unexposed control animals. These changes were associated with an approximately 34% reduction in serotonin (5-hydroxytryptamine [5-HT]) metabolism/inactivation to 5-hydroxyindolacetic acid, and a nearly 40% reduction in monoamine oxidase (MAO)-A activity in the lung. Pretreatment of mice with a selective 5-HT reuptake inhibitor completely ablated the MA-induced changes in pulmonary function, confirming a key role for the 5-HT transporter (serotonin transporter [SERT]) and the serotonergic system in this effect. Immunofluorescent staining of mouse lung tissue confirmed high expression of SERT in airway epithelial cells. Using mouse airway epithelial cell line, LA-4, and purified human MAO-A, it was demonstrated that MA impedes 5-HT metabolism through direct inhibition of MAO-A activity in vitro. Together, these data demonstrate that low-dose exposure to MA results in reduced pulmonary function mediated via SERT and subsequent perturbation of 5-HT metabolism in the lung. This supports a role for the serotonergic system in MA-mediated pulmonary effects.
authors.affiliation: Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska 68198-5910, USA. smwells@unmc.edu
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Wells
authors.forename: Mary C
authors.initials: MC
authors.lastname: Buford
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Porter
authors.forename: Heather L
authors.initials: HL
authors.lastname: Brunell
authors.forename: Melisa
authors.initials: M
authors.lastname: Bunderson-Schelvan
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nevin
authors.forename: Fernando
authors.initials: F
authors.lastname: Cardozo-Pelaez
authors.forename: Andrij
authors.initials: A
authors.lastname: Holian
mesh_terms: D000818:Animals; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D008694:Methamphetamine / Q000008:administration & dosage* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D008995:Monoamine Oxidase / Q000378:metabolism; D012129:Respiratory Function Tests; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013997:Time Factors
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram; D012701:Serotonin; D008694:Methamphetamine; D008995:Monoamine Oxidase