Chronic h1-antihistamine treatment increases seizure susceptibility after withdrawal by impairing glutamine synthetase

Wei Wei Hu, Qi Fang, Zheng Hao Xu, Hai Jing Yan, Ping He, Kai Zhong, Yan Ying Fan, Ying Yang, Xiang Nan Zhang, Chun Yang Zhang, Hiroshi Ohtsu, Tian Le Xu, Zhong Chen

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


Aim: To investigate the effect of chronic H1-antihistamine treatment on seizure susceptibility after drug withdrawal in nonepileptic rats and to further study its relation to glutamine synthetase (GS), which is the key enzyme for glutamate metabolism and gamma aminobutyric acid (GABA) synthesis. Methods: After drug withdrawal from a 2-week treatment with diphenhydramine or pyrilamine, seizure susceptibility was determined by amygdaloid kindling or pentylenetetrazol model; meanwhile, the GS expression or activity was analyzed. The glutamine, glutamate, and GABA contents were measured by high-performance liquid chromatography. Results: Seizure susceptibility significantly increased in amygdaloid kindling and pentylenetetrazol model 10 days after drug withdrawal from a 2-week treatment with H1-antihistamines. Meanwhile, GS activity and expression in the cortex or hippocampus decreased simultaneously with a marked decline of glutamine and GABA content. Comparable inhibition of GS activity by methionine sulfoximine was also sufficient to increase the susceptibility, while supplementation with glutamine reversed the high susceptibility 10 days after diphenhydramine withdrawal. Moreover, the seizure susceptibility increased 10 days after diphenhydramine withdrawal in wild-type mice but not in histidine decarboxylase knockout mice, which lack histamine. Conclusions: Chronic H1-antihistamine treatment produces long-lasting increase in seizure susceptibility in nonepileptic rodents after drug withdrawal and its mechanism involves impairment of GS through blocking the action of histamine.

Original languageEnglish
Pages (from-to)683-690
Number of pages8
JournalCNS Neuroscience and Therapeutics
Issue number8
Publication statusPublished - 2012 Aug


  • Gamma aminobutyric acid
  • Glutamine synthetase
  • H1-antihistamine
  • Seizure susceptibility

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)


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