Abstract
Several lines of evidence indicate that ketamine has a rapid antidepressant-like effect in rodents and humans, but underlying mechanisms are unclear. In the present study, we investigated the effect of ketamine on serotonin (5-HT) release in the rat prefrontal cortex by in vivo microdialysis. A subcutaneous administration of ketamine (5 and 25 mg/kg) significantly increased the prefrontal 5-HT level in a dose-dependent manner, which was attenuated by local injection of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists into the dorsal raphe nucleus (DRN). Direct stimulation of AMPARs in the DRN significantly increased prefrontal 5-HT level, while intra-DRN injection of ketamine (36.5 nmol) had no effect. Furthermore, intra-DRN injection of an α 4 β 2-nicotinic acetylcholine receptor (nAChR) antagonist, dihydro-β-erythroidine (10 nmol), significantly attenuated the subcutaneous ketamine-induced increase in prefrontal 5-HT levels. These results suggest that AMPARs and α 4 β 2-nAChRs in the DRN play a key role in the ketamine-induced 5-HT release in the prefrontal cortex.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antidepressive Agents / administration & dosage
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Antidepressive Agents / pharmacology
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Benzothiadiazines / administration & dosage
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Benzothiadiazines / pharmacology
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Dihydro-beta-Erythroidine / administration & dosage
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Dihydro-beta-Erythroidine / pharmacology
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Dorsal Raphe Nucleus / drug effects*
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Dorsal Raphe Nucleus / metabolism*
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Dose-Response Relationship, Drug
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Injections, Subcutaneous
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Ketamine / administration & dosage
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Ketamine / antagonists & inhibitors
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Ketamine / pharmacology*
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Male
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Microdialysis
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Microinjections
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Nicotinic Antagonists / administration & dosage
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Nicotinic Antagonists / pharmacology
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Prefrontal Cortex / drug effects*
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Prefrontal Cortex / metabolism
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Quinoxalines / administration & dosage
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Quinoxalines / pharmacology
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Rats
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Receptors, AMPA / agonists
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Receptors, AMPA / antagonists & inhibitors
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Receptors, AMPA / metabolism*
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Receptors, Nicotinic / metabolism*
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Serotonin / metabolism*
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Spermine / administration & dosage
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Spermine / analogs & derivatives
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Spermine / pharmacology
Substances
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Antidepressive Agents
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Benzothiadiazines
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Nicotinic Antagonists
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Quinoxalines
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Receptors, AMPA
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Receptors, Nicotinic
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nicotinic receptor alpha4beta2
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2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
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1-naphthylacetylspermine
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Dihydro-beta-Erythroidine
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Spermine
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Serotonin
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Ketamine
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cyclothiazide