Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect

Biol Psychiatry. 2001 May 1;49(9):753-62. doi: 10.1016/s0006-3223(00)01114-8.


Background: Recent studies have demonstrated that chronic antidepressant treatment increases the expression of the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus. The study presented here was conducted to determine if CREB is a relevant target that produces an antidepressant-like effect.

Methods: We employed the herpes simplex virus (HSV)-mediated gene transfer technique to overexpress CREB and determined its effect on the learned helplessness and forced swim tests, two established models used for pharmacological screening of antidepressant drugs.

Results: In the learned helplessness model, rats that received bilateral microinjection of HSV-CREB into the dentate gyrus showed significantly fewer escape failures in the subsequent conditioned avoidance test than those injected with control vector (HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant response. In the forced swim test, CREB expression in the dentate gyrus resulted in a significantly shorter immobility time than those injected with HSV-LacZ.

Conclusions: These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • CREB-Binding Protein
  • Cyclic AMP / metabolism*
  • Dentate Gyrus / metabolism
  • Depression / metabolism
  • Genes, Viral / drug effects
  • Genes, Viral / genetics
  • Genetic Vectors / drug effects
  • Genetic Vectors / genetics
  • Helplessness, Learned
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Imipramine / pharmacology
  • Immunohistochemistry
  • Male
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / metabolism*
  • Prefrontal Cortex / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Simplexvirus / drug effects
  • Simplexvirus / genetics
  • Simplexvirus / metabolism
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism*


  • Antidepressive Agents
  • Nuclear Proteins
  • RNA, Messenger
  • Trans-Activators
  • Cyclic AMP
  • CREB-Binding Protein
  • Crebbp protein, rat
  • Imipramine