Raphe AMPA receptors and nicotinic acetylcholine receptors mediate ketamine-induced serotonin release in the rat prefrontal cortex.
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.
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University,Kyoto,Japan.
Naoya
N
Nishitani
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University,Kyoto,Japan.
Kazuki
K
Nagayasu
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University,Kyoto,Japan.
Nozomi
N
Asaoka
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University,Kyoto,Japan.
Mayumi
M
Yamashiro
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University,Kyoto,Japan.
Hisashi
H
Shirakawa
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University,Kyoto,Japan.
Takayuki
T
Nakagawa
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University,Kyoto,Japan.
Shuji
S
Kaneko
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D001581:Benzothiadiazines / Q000008:administration & dosage / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000008:administration & dosage / Q000494:pharmacology; D065847:Dorsal Raphe Nucleus / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D007649:Ketamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D000928:Antidepressive Agents; D001581:Benzothiadiazines; D018733:Nicotinic Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C067506:1-naphthylacetylspermine; D004079:Dihydro-beta-Erythroidine; D013096:Spermine; D012701:Serotonin; D007649:Ketamine; C004639:cyclothiazide