Pulmonary Vascular Remodeling in Rats Following Methamphetamine Self-Administration: Toward a Model of Methamphetamine-Associated Pulmonary Arterial Hypertension
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ID: 316860
2026
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Abstract
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.
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| Authors | Prangthip Charoenpong, Nicole M Hall, Courtney M. Keller, Ashok Kumar, Ling Chen, J. Gatuz, Najam Siddiqui, Fereshteh Sadat Tabatabaei Yazdi, Daffolyn Rachael Fels Elliott, Navneet K. Dhillon, Kevin S. Murnane, Nicholas E. Goeders, Robert Walter |
| Journal | toxicological sciences : an official journal of the society of toxicology |
| Year | 2026 |
| DOI |
10.1093/toxsci/kfag072
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| URL | |
| Keywords | Keywords not found |
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