Mitochondrial function influences expression of methamphetamine-induced behavioral sensitization

Sci Rep. 2021 Dec 31;11(1):24529. doi: 10.1038/s41598-021-04301-9.


Repeated methamphetamine use leads to long lasting brain and behavioral changes in humans and laboratory rats. These changes have high energy requirements, implicating a role for mitochondria. We explored whether mitochondrial function underpins behaviors that occur in rats months after stopping methamphetamine self-administration. Accordingly, rats self-administered intravenous methamphetamine for 3 h/day for 14 days. The mitochondrial toxin rotenone was administered as (1 mg/kg/day for 6 days) via an osmotic minipump starting at 0, 14 or 28 days of abstinence abstinence. On abstinence day 61, expression of methamphetamine-induced behavioral sensitization was obtained with an acute methamphetamine challenge in rotenone-free rats. Rotenone impeded the expression of sensitization, with the most robust effects obtained with later abstinence exposure. These findings verified that self-titration of moderate methamphetamine doses results in behavioral (and thus brain) changes that can be revealed months after exposure termination, and that the meth-initiated processes progressed during abstinence so that longer abstinence periods were more susceptible to the consequences of exposure to a mitochondrial toxin.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / adverse effects*
  • Locomotion / drug effects
  • Male
  • Methamphetamine / administration & dosage
  • Methamphetamine / adverse effects*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism*
  • Motor Activity / drug effects
  • Rats
  • Rotenone / administration & dosage
  • Rotenone / adverse effects
  • Rotenone / analogs & derivatives
  • Self Administration
  • Time Factors


  • Central Nervous System Stimulants
  • Rotenone
  • rotenolone
  • Methamphetamine