Exploring the progression of drug dependence in a methamphetamine self-administration rat model through targeted and non-targeted metabolomics analyses

• Published in: Scientific reports 2024-09, Vol.14 (1), p.22543-16, Article 22543
• Main Authors: Song, Sang-Hoon, Kim, Suji, Jang, Won-Jun, Ryu, In Soo, Jeong, Chul-Ho, Lee, Sooyeun
• Format: Article
• Language: English
• Subjects: 631/378; 639/638; 692/699; Animal models; Animals; Arginine - administration & dosage; Arginine - metabolism; Biosynthesis; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - adverse effects; Disease Models, Animal; Disease Progression; Drug abuse; Drug dependence; Drug self-administration; Drug withdrawal; Extinction behavior; Extinction, Psychological - drug effects; Glycerophospholipids - metabolism; Humanities and Social Sciences; Male; Mass spectrometry; Metabolic Networks and Pathways - drug effects; Metabolic pathways; Metabolism; Metabolome - drug effects; Metabolomics; Metabolomics - methods; Methamphetamine; Methamphetamine - administration & dosage; Methamphetamine - adverse effects; Monoamines; multidisciplinary; Neurotoxicity; Rats; Rats, Sprague-Dawley; Reinstatement; Science; Science (multidisciplinary); Self Administration; Substance-Related Disorders - metabolism; Therapeutic targets; Tricarboxylic acid cycle; Withdrawal
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-73247-5

Persistent neurochemical and biological disturbances resulting from repeated cycles of drug reward, withdrawal, and relapse contribute to drug dependence. Methamphetamine (MA) is a psychostimulant with substantial abuse potential and neurotoxic effects, primarily affecting monoamine neurotransmitter systems in the brain. In this study, we aimed to explore the progression of drug dependence in rat models of MA self-administration, extinction, and reinstatement through targeted and non-targeted metabolomics analyses. Metabolic profiles were examined in rat plasma during the following phases: after 16 days of MA self-administration (Group M); after 16 days of self-administration followed by 14 days of extinction (Group MS); and after self-administration and extinction followed by a reinstatement injection of MA (Group MSM). Each group of MA self-administration, extinction, and reinstatement induces distinct changes in the metabolic pathways, particularly those related to the TCA cycle, arginine and proline metabolism, and arginine biosynthesis. Additionally, the downregulation of glycerophospholipids and sphingomyelins in Group MSM suggests their potential role in MA reinstatement. These alterations may signify the progressive deterioration of these metabolic pathways, possibly contributing to drug dependence following repeated cycles of drug reward, withdrawal, and relapse. These results provide valuable insights into the metabolic changes associated with MA use at various stages, potentially facilitating the discovery of early diagnostic biomarkers and therapeutic targets for MA use disorders.