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

A partial account of the present study was presented at the 29th Congress of the European College of Neuropsychopharmacology, Vienna 2016 and at the Society for Neuroscience 2017 Annual Meeting.[Background] Sub-anesthetic doses of the non-competitive N-methyl-d-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 (0.25 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.The work leading to these results has received funding from Lundbeck A/S, the Innovation Fund Denmark (4135-00084B), SAF2015-68346-P (Spanish Ministry of Economy and Competitiveness, co-financed by European Regional Development Fund (ERDF)) and (PI12/00156 and PI16/00287)Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness, co-financed by European Regional Development Fund (ERDF)). Support from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) (Instituto de Salud Carlos III) and Generalitat de Catalunya Grup de Recerca Consolidat, 2017SGR717 is also acknowledged.Peer reviewe