Exercise Pills for Drug Addiction: Forced Moderate Endurance Exercise Inhibits Methamphetamine-Induced Hyperactivity through the Striatal Glutamatergic Signaling Pathway in Male Sprague Dawley Rats

Int J Mol Sci. 2021 Jul 30;22(15):8203. doi: 10.3390/ijms22158203.


Physical exercise reduces the extent, duration, and frequency of drug use in drug addicts during the drug initiation phase, as well as during prolonged addiction, withdrawal, and recurrence. However, information about exercise-induced neurobiological changes is limited. This study aimed to investigate the effects of forced moderate endurance exercise training on methamphetamine (METH)-induced behavior and the associated neurobiological changes. Male Sprague Dawley rats were subjected to the administration of METH (1 mg/kg/day, i.p.) and/or forced moderate endurance exercise (treadmill running, 21 m/min, 60 min/day) for 2 weeks. Over the two weeks, endurance exercise training significantly reduced METH-induced hyperactivity. METH and/or exercise treatment increased striatal dopamine (DA) levels, decreased p(Thr308)-Akt expression, and increased p(Tyr216)-GSK-3β expression. However, the phosphorylation levels of Ser9-GSK-3β were significantly increased in the exercise group. METH administration significantly increased the expression of NMDAr1, CaMKK2, MAPKs, and PP1 in the striatum, and exercise treatment significantly decreased the expression of these molecules. Therefore, it is apparent that endurance exercise inhibited the METH-induced hyperactivity due to the decrease in GSK-3β activation by the regulation of the striatal glutamate signaling pathway.

Keywords: GSK-3β; drug abuse; forced endurance exercise; glutamatergic signaling pathway; hyperactivity; methamphetamine.

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Dopamine / metabolism
  • Glutamic Acid / metabolism*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Male
  • Methamphetamine / toxicity*
  • Physical Conditioning, Animal / methods*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Psychomotor Agitation / etiology
  • Psychomotor Agitation / therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Running*
  • Signal Transduction


  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Methamphetamine
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Dopamine