Effects Of Ketamine On Behaviro And Morphology Of Hippocampus And Prefrontal Cortexd In Cynomolgus Monkeys

Objective To explore effects of long-term low-dose ketamine administration on behavior and morphology of hippocampus and prefrontal cortex in Cynomolgus Monkeys.Methods 12 male healthy Cynomolgus Monkeys were randomly divided into ketamine group (8) and control group (4). Ketamine group was injected intravenously daily with the dose of ketamine (1mg/kg), while control group was injected intravenously daily with normal saline (1ml/kg). Fifteen minutes spontaneous locomotor activities were observed after each injection recording at day 1, day 3, day 7, day 14, day 56, day 112, day 183, day 184 and day 185. Six months later,3 Cynomolgus Monkeys from ketamine group and 1 Cynomolgus Monkey from control group were randomly chosen to be sacrificed, being perfused with 4% paraformaldehyde. Hippocampus and prefrontal cortex of each Cynomolgus Monkey were dissected after craniotomy. Hematoxylin-eosin staining of hippocampus and prefrontal cortex was used to study morphological changes under light microscope; TUNEL was used to count numbers of apoptotic cells; Ultrastructural changes were observed under transmission electron microscope.Results1. There was no significant differences of locomotor activities (including walking, climbing, moving, jumping) between two groups, but activities of walking, climbing and moving of ketamine group exhibited a obvious decreased tendency as time went by.2. Hematoxylin-eosin staining:Compared with the control group, CA3 and denate gyrus subfields of hippocampus of Cynomolgus Monkeys in ketamine group showed decreased numbers of cells, disturbed cell alignment, increased intercellular space, karyopyknosis of the partial cells, abated cell layers, especially significant in DG subfield. Furthermore, there were more glial cells accumulation forming glial scar instead of granulocytes in DG. Prefrontal cortex of ketamine group exhibited karyopyknosis of partial pyramidal cells, as well as cytoplasmic acidophilic changes.3. TUNEL:There were no significant differences of apoptotic cells between two groups in hippocampus and prefrontal cortex.4. Ultrastructural changes in ketamine group, such as neuron necrosis, glial cell karyopyknosis, accumulation of lipofuscin appeared in hippocampus and a mass of autophagosome, reduction of rough endoplasmic reticulum, neuron necrosis, glial cell karyopyknosis were observed in prefrontal cortex, while those of control group were not observed.Conclusion1. There was a declined trend in locomotor activities of Cynomolgus Monkeys of ketamine group, indicating the tolerance induction of ketamine as time went by.2. Long-term low-dose ketamine administration induced morphological changes in hippocampus and prefrontal cortex, including neurodegenaration, necrosis and apoptosis, those pathological morphological changes in main brain areas may underlie impairments of cognition as well as behavior of ketamine users.