Raphe AMPA receptors and nicotinic acetylcholine receptors mediate ketamine-induced serotonin release in the rat prefrontal cortex

• Published in: The international journal of neuropsychopharmacology Vol. 17; no. 8; pp. 1321 - 1326
• Main Authors: Nishitani, Naoya, Nagayasu, Kazuki, Asaoka, Nozomi, Yamashiro, Mayumi, Shirakawa, Hisashi, Nakagawa, Takayuki, Kaneko, Shuji
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.08.2014; Oxford University Press
• Subjects: Animals; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Benzothiadiazines - administration & dosage; Benzothiadiazines - pharmacology; Dihydro-beta-Erythroidine - administration & dosage; Dihydro-beta-Erythroidine - pharmacology; Dorsal Raphe Nucleus - drug effects; Dorsal Raphe Nucleus - metabolism; Dose-Response Relationship, Drug; Injections, Subcutaneous; Ketamine - administration & dosage; Ketamine - antagonists & inhibitors; Ketamine - pharmacology; Male; Microdialysis; Microinjections; Nicotinic Antagonists - administration & dosage; Nicotinic Antagonists - pharmacology; Prefrontal Cortex - drug effects; Prefrontal Cortex - secretion; Quinoxalines - administration & dosage; Quinoxalines - pharmacology; Rats; Receptors, AMPA - agonists; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - metabolism; Receptors, Nicotinic - metabolism; Serotonin - secretion; Spermine - administration & dosage; Spermine - analogs & derivatives; Spermine - pharmacology; Ketamine; AMPA receptors; α 4 β 2-nicotinic acetylcholine receptors; Serotonin; Dorsal raphe nucleus
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1017/S1461145714000649

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.