Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex

Brain Res. 1997 Jun 13;759(2):205-12. doi: 10.1016/s0006-8993(97)00255-2.


Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine / metabolism*
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Male
  • Microdialysis
  • Prefrontal Cortex / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism*
  • gamma-Aminobutyric Acid / metabolism*


  • Serotonin
  • gamma-Aminobutyric Acid
  • Ketamine
  • Dopamine