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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.

SUBMITTER: Wells SM

PROVIDER: S-EPMC2874440 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Role of the serotonergic system in reduced pulmonary function after exposure to methamphetamine.

Wells Sandra M SM Buford Mary C MC Porter Virginia M VM Brunell Heather L HL Bunderson-Schelvan Melisa M Nevin Andrew B AB Cardozo-Pelaez Fernando F Holian Andrij A

American journal of respiratory cell and molecular biology 20090618 5

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 contro ...[more]

PMID: 19541843

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Project description:Background Both ventilatory abnormalities and pulmonary hypertension (PH) are frequently observed in patients with heart failure with reduced ejection fraction. We aim to investigate the association between ventilatory abnormalities and PH in heart failure with reduced ejection fraction, as well as their prognostic impacts. Methods and Results A total of 440 ambulatory patients (age, 66.2±15.8 years; 77% men) with left ventricular ejection fraction ≤40% who underwent comprehensive echocardiography and spirometry were enrolled. Total lung capacity, forced vital capacity, and forced expiratory volume in the first second were obtained. Pulmonary arterial systolic pressure was estimated. PH was defined as a pulmonary arterial systolic pressure of >50 mm Hg. The primary end point was all-cause mortality at 5 years. Patients with PH had significantly reduced total lung capacity, forced vital capacity, and forced expiratory volume in the first second. During a median follow-up of 25.9 months, there were 111 deaths. After accounting for age, sex, body mass index, renal function, smoking, left ventricular ejection fraction, and functional capacity, total lung capacity (hazard ratio [HR] per 1 SD, 0.66; 95% CI per 1 SD, 0.46-0.96), forced vital capacity (HR per 1 SD, 0.64; 95% CI per 1 SD, 0.48-0.84), and forced expiratory volume in the first second (HR per 1 SD, 0.72; 95% CI per 1 SD, 0.53-0.98) were all significantly correlated with mortality in patients without PH. Kaplan-Meier curve demonstrated impaired pulmonary function, defined as forced expiratory volume in the first second ≤58% of predicted or forced vital capacity ≤65% of predicted, was associated with higher mortality in patients without PH (HR, 2.85; 95% CI, 1.66-4.89), but not in patients with PH (HR, 1.05; 95% CI, 0.61-1.82). Conclusions Ventilatory abnormality was more prevalent in patients with heart failure with reduced ejection fraction with PH than those without. However, such ventilatory defects were related to long-term survival only in patients without PH, regardless of their functional status.

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Role of the serotonergic system in reduced pulmonary function after exposure to methamphetamine.

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Role of the serotonergic system in reduced pulmonary function after exposure to methamphetamine.

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