Abstract
RationaleNumerous preclinical and clinical studies have reported the rapid and sustained antidepressant effects of the NMDA receptor antagonist ketamine. Because ketamine induces several undesirable and dangerous effects, a variety of strategies have been suggested to avoid such effects.ObjectivesHere, we propose to enhance the sub-effective doses of ketamine by co-administration with the group II metabotropic glutamate (mGlu) receptor antagonist LY341495. This compound potentially acts as an antidepressant via a mechanism similar to that of ketamine.MethodsTo investigate the rapid and sustained antidepressant-like effects of these drugs, we administered ketamine and LY341495 individually or in combination, 40 min and 24 h before the forced swim test (FST).ResultsWe found that sub-effective doses of ketamine and LY341495, given jointly, induce significant antidepressant-like effects, at both 40 min and 24 h after administration. The results obtained using Western blot technique indicate that mammalian target of rapamycin (mTOR) pathway activation may be involved in the mechanism of this action. The effects of drugs, used at identical ranges of times and doses, on spontaneous locomotor activity in rats were excluded. Furthermore, the results obtained from the rota-rod test and the ketamine-induced hyperlocomotion test suggest a lack of potentially adverse effects from the combined administration of ketamine and LY341495 at doses previously used in the FST.ConclusionAltogether, these data suggest that the joint administration of ketamine and LY341495 might be a noteworthy alternative to the use of solely ketamine in the therapy of depression.
Highlights
The current treatment of depression is based on the modulation of biogenic amine systems and requires the long-term administration (3–6 weeks) of antidepressant drugs (ADs) in order to obtain positive therapeutic effects (Millan 2006)
The objective of our study was to investigate whether a group II metabotropic glutamate (mGlu) receptor antagonist, LY341495, enhances the rapid and sustained antidepressant-like effects of ketamine
Based on the results obtained during determination of the dose–effect curves, sub-effective doses of both substances (3 mg/kg for ketamine and 0.1 mg/kg for LY341495) were chosen for joint administration
Summary
The current treatment of depression is based on the modulation of biogenic amine systems and requires the long-term administration (3–6 weeks) of antidepressant drugs (ADs) in order to obtain positive therapeutic effects (Millan 2006). Psychopharmacology (2016) 233:2901–2914 stimulates TrkB receptors and leads to fast activation of the mammalian target of rapamycin (mTOR) signaling pathway, resulting in the augmentation of the synaptogenesis in the prefrontal cortex (PFC) (Duman et al 2012; Li et al 2010). According to this hypothesis, enhanced synaptogenesis as a result of the activation of the mTOR cascade appears to be a key mechanism of the rapid and sustained antidepressant action of ketamine. Several studies have shown that functional synaptic changes in the PFC, which appear 24 h after ketamine administration, correlate with the antidepressant effects of the drug in animal models of depression (Koike et al 2011; Li et al 2010; Maeng et al 2008)
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