Abstract Background Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by pulmonary vascular remodeling. Methamphetamine (MA) exposure is strongly associated with PAH in humans, yet prior animal models rely on fixed, non-contingent dosing that does not replicate binge/crash patterns of human MA use. This study introduces an intravenous MA self-administration model to evaluate pulmonary vascular and cardiac consequences of human-like MA exposure. Methods Sixteen male Wistar rats underwent an 8-week protocol in which eight rats self-administered MA and eight yoked-saline controls received volume-matched saline. MA intake, lever-press behavior, and binge/crash dynamics were quantified. Lungs and hearts were harvested for histology, immunofluorescence, medial wall thickness quantification across vessel sizes, ventricular weights, and Fulton index. Results MA-exposed rats demonstrated escalating intake, with daily self-administered doses increasing from early-week values to a cumulative exposure of 526.7 ± 217.8 mg/kg over eight weeks. Distinct binge-and-crash patterns emerged as intake escalated over the exposure period. Compared with controls, MA-exposed rats exhibited pulmonary vascular remodeling predominantly in distal vessels, including medial hypertrophy, increased muscularization of small arterioles, and focal endothelial proliferation. Additional airway-centered parenchymal changes were observed in a subset of MA rats. No significant differences were found in right or left ventricular weights or Fulton index. Conclusion Chronic MA self-administration induces early pulmonary vascular remodeling without cardiac hypertrophy, indicating that this behaviorally relevant model captures early pulmonary vascular changes relevant to MA-associated pulmonary vascular disease. This model provides a translational platform for investigating MA-induced pulmonary vascular injury and identifying therapeutic targets.
Charoenpong et al. (Wed,) studied this question.