Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture.
Administration of subanesthetic concentrations of ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) type of glutamate receptors, is a widely accepted therapeutic modality in perioperative and chronic pain management. Although extensive clinical use has demonstrated its safety, recent human histopathological observations as well as laboratory data suggest that ketamine can exert adverse effects on central nervous system neurons. To further investigate this issue, the present study was designed to evaluate the effects of ketamine on the survival and dendritic arbor architecture of differentiated gamma-aminobutyric acidergic (GABAergic) interneurons in vitro. We show that short-term exposure of cultures to ketamine at concentrations of > or =20 microg/ml leads to a significant cell loss of differentiated cells and that non-cell death-inducing concentrations of ketamine (10 microg/ml) can still initiate long-term alterations of dendritic arbor in differentiated neurons, including dendritic retraction and branching point elimination. Most importantly, we also demonstrate that chronic (>24 h) administration of ketamine at concentrations as low as 0.01 microg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal morphology and thus might lead to dysfunctions of neural networks.
Vutskits
Laszlo
L
Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. laszlo.vutskits@hcuge.ch
Gascon
Eduardo
E
Potter
Gael
G
Tassonyi
Edomer
E
Kiss
Jozsef Z
JZ
D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000473:pathology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007649:Ketamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D016291:Dizocilpine Maleate