Abstract
Ketamine is an anesthetic and a popular abusive drug. As an anesthetic, effects of ketamine on glutamate and GABA transmission have been well documented but little is known about its long-term effects on the dopamine system. In the present study, the effects of ketamine on dopamine were studied in vitro and in vivo. In pheochromocytoma (PC 12) cells and NGF differentiated-PC 12 cells, ketamine decreased the cell viability while increasing dopamine (DA) concentrations in a dose-related manner. However, ketamine did not affect the expression of genes involved in DA synthesis. In the long-term (3 months) ketamine treated mice, significant increases of DA contents were found in the midbrain. Increased DA concentrations were further supported by up-regulation of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Activation of midbrain dopaminergic neurons could be related to ketamine modulated cortical-subcortical glutamate connections. Using western blotting, significant increases in BDNF protein levels were found in the midbrain, suggesting that perhaps BDNF pathways in the cortical-subcortical connections might contribute to the long-term ketamine induced TH upregulation. These data suggest that long-term ketamine abuse caused a delayed and persistent upregulation of subcortical DA systems, which may contribute to the altered mental status in ketamine abusers.
Highlights
Ketamine has become a popular recreational drug in many parts of the world in recent years due to its psychosis-like effects and cheap prices [1]
Cell culture and ketamine treatment Rat pheochromocytoma 12 (PC12) cells were obtained from the American Tissue Culture Collection (ATCC) and were grown in Ham’s F-12K (Kaighn’s modifications, Invitrogen) medium supplement with 10% heat-inactivated horse serum and 5% fetal bovine serum
These results indicated that d-PC12 cells were less susceptible to ketamine’s toxicity than undifferentiated PC12 cells
Summary
Ketamine has become a popular recreational drug in many parts of the world in recent years due to its psychosis-like effects and cheap prices [1]. In Hong Kong, ketamine abuse has increased rapidly over the last decade and is the most abused psychotropic substance. The most recent data from the Central Registry of Drug Abuse (CRDA) indicated that 31.5% of all the abused drugs are ketamine in Hong Kong in 2011 [2]. Ketamine modulates neurotransmission at postsynaptic receptors such as N-methyl-D-aspartate (NMDA) glutamate receptors and gamma-aminobutryic acid (GABA) receptors. Ketamine blocks NMDA receptor and induces a dissociative anesthesia [6]. Ketamine-induced anesthesia was thought to work via enhancing the GABA inhibitory neurotransmission in the central nervous system (CNS) [7]. In our previous study, upregulated GABA(A) receptors were found in prolonged ketamine treated mice brain, suggesting that long-term ketamine administration increased the GABA inhibitory transmission in the CNS [9]
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