Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus

Neuropsychopharmacology. 2003 Jan;28(1):53-62. doi: 10.1038/sj.npp.1300009.


It has been proposed that antidepressants have neuroprotective effects on hippocampal neurons. To further test this hypothesis, brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5 or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline and venlafaxine increased the intensity of BDNF immunostaining in hippocampal pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine, however, decreased the intensity of BDNF immunostaining in all subareas of the hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate granular cell layer. The high dose of amitriptyline increased the intensity of Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or BDNF. These findings suggest that the chronic administration of amitriptyline or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal neurons. These dose-related effects of antidepressant drugs on hippocampal neurons may have relevance to disparate findings in the field.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amitriptyline / pharmacology
  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents, Tricyclic / pharmacology
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cyclohexanols / pharmacology
  • Densitometry
  • Dose-Response Relationship, Drug
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Hippocampus / metabolism*
  • Immunohistochemistry
  • Male
  • Neuroprotective Agents / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin Uptake Inhibitors / pharmacology
  • Superoxide Dismutase / metabolism*
  • Venlafaxine Hydrochloride
  • Weight Gain / drug effects


  • Antidepressive Agents
  • Antidepressive Agents, Tricyclic
  • Brain-Derived Neurotrophic Factor
  • Cyclohexanols
  • Neuroprotective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Serotonin Uptake Inhibitors
  • Amitriptyline
  • Venlafaxine Hydrochloride
  • Superoxide Dismutase