Temporally dissociable effects of ketamine on neuronal discharge and gamma oscillations in rat thalamo-cortical networks

NEUROPHARMACOLOGY

卷:137

Article

Amat-Foraster, Maria^1,2,3,5  Jensen, Anders A.²  Plath, Niels¹  Herrik, Kjartan F.¹  Celada, Pau^3,4,5  Artigas, Francesc^3,4,5 

[1] H Lundbeck & Co AS, Synapt Transmiss, Valby, Denmark

[2] Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark

[3] Inst Invest Biomed Barcelona IIBB CSIC, Dept Neurochem & Neuropharmacol, Barcelona, Spain

[4] CIBERSAM, Ctr Invest Biomed Red Salud Mental, Barcelona, Spain

[5] IDIBAPS, Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain

关键词: NMDA receptor antagonists;    Ketamine;    Thalamo-cortical networks;    Neuronal oscillations;    Single unit recordings;    Local field potentials;   

DOI  :  10.1016/j.neuropharm.2018.04.022

来源: Elsevier

【 摘 要 】

Background: Sub-anesthetic doses of the non-competitive N-methyl-o-aspartate receptor (NMDA-R) antagonist ketamine evoke transient psychotomimetic effects, followed by persistent antidepressant effects in treatment-resistant depressed patients and rodents through still poorly understood mechanisms. Since phencyclidine (PCP) disinhibits thalamo-cortical networks by blocking NMDA-Rs on GABAergic neurons of the reticular thalamic nucleus (RtN), we examined ketamine's actions in the same areas. Methods: Single units and local field potentials were recorded in chloral hydrate anesthetized male Wistar rats. The effects of cumulative ketamine doses (0.25-5 mg/kg, i.v.) on neuronal discharge and oscillatory activity were examined in RtN, mediodorsal and centromedial (MD/CM) thalamic nuclei, and layer VI of the medial prefrontal cortex (mPFC). Results: Ketamine (1, 2 and 5 mg/kg, i.v.) significantly decreased the discharge of MD/CM, RtN and layer VI mPFC pyramidal neurons. Simultaneously, ketamine decreased the power of low frequency oscillations in all areas examined and increased gamma oscillations in mPFC and MD/CM. Lower ketamine doses (025 and 0.5 mg/kg, i.v.) were ineffective. Conclusions: As observed for PCP, ketamine markedly inhibited the activity of RtN neurons. However, unlike PCP, this effect did not translate into a disinhibition of MD/CM and mPFC excitatory neurons, possibly due to a more potent and simultaneous blockade of NMDA-Rs by ketamine in MD/CM and mPFC neurons. Hence, the present in vivo results show that ketamine evokes an early transient inhibition of neuronal discharge in thalamo-cortical networks, following its rapid pharmacokinetics, which is likely associated to its psychotomimetic effects. The prolonged increase in gamma oscillations may underlie its antidepressant action. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

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