Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels

Mol Psychiatry. 1999 Sep;4(5):443-52. doi: 10.1038/


alpha2-Adrenoceptors (alpha2-AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three alpha2-AR subtypes (alpha2A, alpha2B, and alpha2C) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, alpha2-AR subtype-selective pharmacological probes are not available, mice with genetically altered alpha2C-AR expression were studied in order to investigate the possible involvement of the alpha2C-AR in physiological and behavioral responses to acute and repeated stress. A modified version of Porsolt's forced swimming test was used to assess the possible effects of altered alpha2C-AR expression on the development of behavioral despair. alpha2C-Overexpression increased and the lack of alpha2C-AR (alpha2C-KO) decreased the immobility of mice in the forced swimming test, ie alpha2C-AR expression appeared to promote the development of behavioral despair. In addition, alpha2C-KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of alpha2C-ARs was linked with increased corticosterone levels after repeated stress. Moreover, the brain dopamine and serotonin balance, but not norepinephrine turnover, was dependent on alpha2C-AR expression, and the expression of c-fos and junB mRNA was increased in alpha2C-KO mice. Since alpha2C-KO produced stress-protective effects, and alpha2C-AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective alpha2C-AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / analysis
  • Animals
  • Behavior, Animal / physiology*
  • Cerebral Cortex / chemistry
  • Corpus Striatum / chemistry
  • Corticosterone / blood*
  • Depression / genetics
  • Depression / physiopathology
  • Dopamine / analysis
  • Genes, Immediate-Early / physiology
  • Genetic Markers
  • Hippocampus / chemistry
  • Homovanillic Acid / analysis
  • Hydroxyindoleacetic Acid / analysis
  • In Situ Hybridization
  • Methoxyhydroxyphenylglycol / analysis
  • Mice
  • Mice, Transgenic
  • Norepinephrine / analysis
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • RNA, Messenger / analysis
  • Receptors, Adrenergic, alpha-2 / genetics*
  • Restraint, Physical
  • Serotonin / analysis
  • Stress, Physiological / genetics
  • Stress, Physiological / physiopathology*
  • Swimming


  • Genetic Markers
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Receptors, Adrenergic, alpha-2
  • 3,4-Dihydroxyphenylacetic Acid
  • Serotonin
  • Methoxyhydroxyphenylglycol
  • Hydroxyindoleacetic Acid
  • Dopamine
  • Corticosterone
  • Norepinephrine
  • Homovanillic Acid