Water-restraint stress enhances methamphetamine-induced cardiotoxicity

Masafumi Tomita, Hironobu Katsuyama, Yoko Watanabe, Kazuo Hidaka, Kei Yoshitome, Satoru Miyaishi, Takaki Ishikawa, Kotaro Shinone, Masayuki Nata

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


Methamphetamine (MAP) and stress both cause a variety of cardiovascular problems. Stress also increases stimulant drug-seeking or drug-taking behavior by both humans and animals. In addition to the physiological effects on circulation, metabolism, and excretion, stress affects subject's responses to stimulant drugs such as MAP. However, the mechanisms underlying the drug-stress interactions remain unknown. In the present study, we assessed the effects of stress on myocardial responses to MAP in mice. Mice were injected with MAP (30 mg/kg) immediately before exposure to water-restraint stress (WRS), which has often been used as a stressor in animal experiments. The combination of MAP with WRS produced a significant increase (p < 0.01) in the leakage of proteins specific to myocardial damage and the levels of cytokines IL-6, TNF-α, and IL-10. The histological findings indicated the possibility that a combination of MAP with WRS induced cardiac myocytolysis. We also examined the expression of heat shock proteins (Hsps), which have cardioprotective effects. Administration of MAP alone significantly stimulated the RNA expressions of Hsp32, 60, 70, and 90 and the protein Hsp70 in cardiac muscles, whereas the expressions due to WRS or MAP plus WRS were not increased. These results reveal the fact that exposure to WRS depresses the induction of Hsps, in particular Hsp70, due to MAP injection, following to enhance MAP-induced myocardial damage. We believe that interactions between MAP and severe stress, including environmental temperature, affect the induction of Hsps, following to susceptibility of hosts to cardiotoxicity due to the stimulant drug.

Original languageEnglish
Pages (from-to)54-61
Number of pages8
JournalChemico-Biological Interactions
Issue number1
Publication statusPublished - Mar 15 2011


  • Cardiotoxicity
  • Heat shock protein
  • Methamphetamine
  • Myocardia
  • Water-restraint stress

ASJC Scopus subject areas

  • Toxicology


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