Chronic hypobaric hypoxia induces tolerance to acute hypoxia and up-regulation in alpha-2 adrenoceptor in rat locus coeruleus

Brain Res. 2006 Aug 23;1106(1):82-90. doi: 10.1016/j.brainres.2006.05.112. Epub 2006 Jul 13.


Hypoxia preconditioning has been shown to produce tolerance against brain injuries. The hypothesis of this study is that chronic hypobaric hypoxia may also induce acute hypoxia tolerance. We used intracellular recording in slices from rats exposed to chronic hypobaric hypoxia (exposed) and control to investigate the effects of chronic hypobaric hypoxia on the physiology of locus coeruleus (LC) including neuronal excitability. The results showed 35.7% reduced spontaneous firing rate and no change for membrane potential and input resistance in exposed neurons. In response to the alpha-2 adrenoceptor (A2R) agonist clonidine, both the hyperpolarizing potency and efficacy were increased indicated by a decreased EC(50) (control: 30.9 nM and exposed: 19.7 nM) and a 50.5% increase in maximum hyperpolarized potential, respectively. A2R binding sites were also increased 21% in exposed neurons measured by radioligand [(3)H]rauwolscine binding assay. When treated with acute N(2)-hypoxia, the cell survival time (ST) was longer in exposed neurons, suggesting that a tolerance was induced. In addition, the ST for both groups of LC neurons was decreased by the A2R antagonist yohimbine and increased by the glutamate receptor antagonist kynurenic acid but not by MK-801; the decreased percentage of ST by yohimbine was larger and the increased percentage by kynurenic acid was smaller in exposed neurons. The results suggested that up-regulation of A2R and altered non-NMDA glutamate receptor function induced by chronic hypobaric hypoxia may underlie, in part, the decreased LC neuronal excitability and acute hypoxia tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Acute Disease
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Binding, Competitive / drug effects
  • Binding, Competitive / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Chronic Disease
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hypoxia, Brain / metabolism*
  • Hypoxia, Brain / physiopathology
  • Ischemic Preconditioning / methods*
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism*
  • Male
  • Norepinephrine / metabolism
  • Organ Culture Techniques
  • Oxygen Consumption / physiology
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Receptors, Glutamate / drug effects
  • Receptors, Glutamate / metabolism
  • Up-Regulation / drug effects*
  • Up-Regulation / physiology


  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Excitatory Amino Acid Antagonists
  • Receptors, Adrenergic, alpha-2
  • Receptors, Glutamate
  • Norepinephrine