Abstract
Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in human patients and ameliorates depressive-like behavioral effects of chronic stress in animal models. Chronic stress and elevated corticosterone levels have been shown to modify serotonin (5-HT) neurotransmission, and ketamine's antidepressant-like activity involves a 5-HT-dependent mechanism. However, it is not known if and how ketamine affects the electrophysiological characteristics of neurons and synaptic transmission within the dorsal raphe nucleus (DRN), the main source of 5-HT forebrain projections. Our study was aimed at investigating the effects of a single ketamine administration on excitatory and inhibitory transmission in the DRN of rats which had previously been administered corticosterone twice daily for 7 days. Spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) were then recorded from DRN projection cells in ex vivo slice preparations obtained 24 h after ketamine injection. Repeated corticosterone administration increased sEPSC frequency and decreased sIPSC frequency in DRN projection cells. There were no changes either in the amplitude of postsynaptic currents or in the excitability of these cells. In slices prepared from rats with ketamine administered after the end of corticosterone treatment, the frequencies of sEPSCs and sIPSCs were similar to those in control preparations. These data indicate that a single administration of ketamine reversed the effects of corticosterone on excitatory and inhibitory transmission in the DRN.
Highlights
It has been well documented that administering ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, to patients suffering from major depressive disorder and bipolar depression induces rapid antidepressant effects ([1] reviewed in [2, 3, 4])
We have recently demonstrated that repeated corticosterone administration weakened GABAergic inputs to rat dorsal raphe nucleus (DRN) projection neurons by decreasing the frequency of spontaneous inhibitory postsynaptic currents [27]
We report that repeated injections of corticosterone increased sEPSC frequency and decreased spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from putative DRN 5-HT projection neurons
Summary
It has been well documented that administering ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, to patients suffering from major depressive disorder and bipolar depression induces rapid antidepressant effects ([1] reviewed in [2, 3, 4]). Antidepressant actions of ketamine are currently thought to be related to a rapid, transient increase in the extracellular glutamate level in the medial prefrontal cortex (mPFC) This leads to activity-dependent release of the brain-derived neurotrophic factor (BDNF), followed by the activation of tyrosine receptor kinase B (TrkB) receptors and mammalian target of rapamycin- (mTOR-) dependent intracellular signaling cascades. These mechanisms promote the strengthening of excitatory synapses in the mPFC and in subcortical reward circuits ([10] reviewed in [11, 12, 13])
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