title: Mechanisms underlying ketamine-induced synaptic depression in rat hippocampus-medial prefrontal cortex pathway.
abstract: The non-competitive N-methyl-D-aspartate NMDA receptor antagonist ketamine, a dissociative anesthetic capable of inducing analgesia, is known to have psychotomimetic actions, but the detailed mechanisms remain unclear because of its complex properties. The present study elucidated neural mechanisms of the effect of ketamine, at doses that exert psychotomimetic effects without anesthetic and analgesic effects, by evaluating cortical synaptic responses in vivo. Systemic administration (i.p.) of low (1 and 5 mg/kg), subanesthetic (25 mg/kg) and anesthetic (100 mg/kg) doses of ketamine dose-dependently decreased hippocampal stimulation-evoked potential in the medial prefrontal cortex (mPFC) in freely moving rats. The behavioral analysis assessed by prepulse inhibition (PPI) of acoustic startle response showed that ketamine (5 and 25 mg/kg, i.p.) produced PPI deficit. Thus, the psychotomimetic effects observed in ketamine-treated groups (5 and 25 mg/kg, i.p.) are associated with the induction of synaptic depression in the hippocampus-mPFC neural pathway. Based on these results, we further examined the underlying mechanisms of the ketamine-induced synaptic depression under anesthesia. Ketamine (5 and 25 mg/kg, i.p.) caused increases in dialysate dopamine in the mPFC in anesthetized rats. Moreover, the ketamine-induced decreases in the evoked potential, at the dose 5 mg/kg which has no anesthetic and analgesic effects, were indeed absent in dopamine-lesioned rats pretreated with 6-hydroxydopamine (6-OHDA; 150 μg/rat, i.c.v.). Ketamine (5 mg/kg, i.p.)-induced synaptic depression was blocked by pretreatment with dopamine D1 receptor antagonist SCH 23390 (10 μg/rat, i.c.v.) but not dopamine D2 receptor antagonist haloperidol (1.5 mg/kg, i.p.), suggesting that dopaminergic modulation mediated via D1 receptors are involved in the synaptic effects of ketamine. Furthermore, ketamine (5 mg/kg, i.p.)-induced synaptic depression was prevented also by GABAA receptor antagonist bicuculline (0.2 or 2 μg/rat, i.c.v.). These findings suggest that ketamine at the dose that exerts psychotomimetic symptoms depresses hippocampus-mPFC synaptic transmission through mechanisms involving dopaminergic modulation mediated via D1 receptors, which may lead to a net augmentation of synaptic inhibition mediated via GABAA receptors.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, 061-0293, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kamiyama
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Otani
authors.forename: S-I
authors.initials: SI
authors.lastname: Kimura
authors.forename: K-I
authors.initials: KI
authors.lastname: Shimamura
authors.forename: S
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: H
authors.initials: H
authors.lastname: Togashi
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007649:Ketamine