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.

Fluoxetine protects against methamphetamine-induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats

“…In a previous study (6), it was identified that MA induced the increasedconcentration of 5-HT, which indicated that the serotonin mechanism is involved in MA-induced pulmonary toxicity. MA, as a substrate for SERT, was transported into cells and subsequently inhibited the metabolism of 5-HT by inhibiting monoamine oxidase A (6,27). The activation of SERT can promote 5-HT-impaired efferocytosis (11).…”

Fluoxetine Attenuates Chronic Methamphetamine‐induced Pulmonary Arterial Remodelling: Possible Involvement of Serotonin Transporter and Serotonin 1B Receptor

“…It had been found that MA has multiple effects on the serotonergic signalling and 5-HT is capable of contributing to the development of PAH [8]. However, the effect of MA on the pulmonary vessels has not been directly investigated.…”

“…routes where very high levels of drug would be expected to interact with the serotonergic system in the lung [1]. Depending on the degree of retention by the lung, intrinsic toxicity and individual susceptibility, pulmonary hypertension might develop as a toxic response to MA [8,27].…”

“…Methamphetamine, a substituted amphetamine with potent central nervous system effects [8], evokes the release of 5-HT from neurons by acting as 5-HTT substrates that reverse the normal direction of transmitter flux [9,10]. Moreover, extensive experimental animal research showed that MA caused release of serotonin in brain [11].…”

IL-1R signalling is critical for regulation of multi-walled carbon nanotubes-induced acute lung inflammation in C57Bl/6 mice

“…Transpulmonary resistance was assessed as previously described (Wells et al 2010). Mice were challenged with vehicle (PBS), followed by increasing concentrations of methacholine (1.5, 3, 6, 12 and 24 mg/ml).…”