Serotonin depletion can enhance the cerebrovascular responses induced by cortical spreading depression via the nitric oxide pathway

Int J Neurosci. 2015 Feb;125(2):130-9. doi: 10.3109/00207454.2014.908876. Epub 2014 May 19.


Serotonin (5-HT) is an important neurotransmitter involved in the control of neural and vascular responses. 5-HT depletion can induce several neurological disorders, including migraines. Studies on a cortical spreading depression (CSD) migraine animal model showed that the cortical neurons sensitivity, vascular responses, and nitric oxide (NO) production were significantly increased in 5-HT depletion. However, the involvement of NO in the cerebrovascular responses in 5-HT depletion remains unclear. This study aimed to investigate the role of NO in the CSD-induced alterations of cerebral microvessels in 5-HT depletion. Rats were divided into four groups: control, control with L-NAME treatment, 5-HT depleted, and 5-HT depleted with L-NAME treatment. 5-HT depletion was induced by intraperitoneal injection with para-chlorophenylalanine (PCPA) 3 days before the experiment. The CSD was triggered by KCl application. After the second wave of CSD, N-nitro-l-arginine methyl ester (L-NAME) or saline was intravenously injected into the rats with or without L-NAME treatment groups, respectively. The intercellular adhesion molecules-1 (ICAM-1), cell adhesion molecules-1 (VCAM-1), and the ultrastructural changes of the cerebral microvessels were examined. The results showed that 5-HT depletion significantly increased ICAM-1 and VCAM-1 expressions in the cerebral cortex. The number of endothelial pinocytic vesicles and microvilli was higher in the 5-HT depleted group when compared to the control. Interestingly, L-NAME treatment significantly reduced the abnormalities observed in the 5-HT depleted group. The results of this study demonstrated that an increase of NO production is one of the mechanisms involved in the CSD-induced alterations of the cerebrovascular responses in 5-HT depletion.

Keywords: cortical spreading depression; endothelial cell; serotonin depletion; ultrastructural changes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Cerebrovascular Circulation / drug effects
  • Cerebrovascular Circulation / physiology*
  • Cortical Spreading Depression / drug effects
  • Cortical Spreading Depression / physiology*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Intercellular Adhesion Molecule-1 / metabolism
  • Male
  • Methamphetamine / analogs & derivatives
  • Methamphetamine / pharmacology
  • Microscopy, Electron, Transmission
  • Microvessels / pathology
  • Microvessels / ultrastructure
  • Migraine Disorders / chemically induced
  • Migraine Disorders / pathology
  • Migraine Disorders / physiopathology*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • NG-Nitroarginine Methyl Ester / toxicity
  • Potassium Chloride
  • Rats
  • Rats, Wistar
  • Serotonin / deficiency*
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Enzyme Inhibitors
  • Vascular Cell Adhesion Molecule-1
  • chlormethamphetamine
  • Intercellular Adhesion Molecule-1
  • Serotonin
  • Methamphetamine
  • Potassium Chloride
  • NG-Nitroarginine Methyl Ester