Abstract
Ketamine produces a rapid antidepressant response in patients with major depressive disorder (MDD), but the underlying mechanisms appear multifaceted. One hypothesis, proposes that by antagonizing NMDA receptors on GABAergic interneurons, ketamine disinhibits afferens to glutamatergic principal neurons and increases extracellular glutamate levels. However, ketamine seems also to reduce rapid glutamate release at some synapses. Therefore, clinical studies in MDD patients have stressed the need to identify mechanisms whereby ketamine decreases presynaptic activity and glutamate release. In the present study, the effect of ketamine and its antidepressant metabolite, (2R,6R)-HNK, on neuronally derived glutamate release was examined in rodents. We used FAST methodology to measure depolarization-evoked extracellular glutamate levels in vivo in freely moving or anesthetized animals, synaptosomes to detect synaptic recycling ex vivo and primary cortical neurons to perform functional imaging and to examine intracellular signaling in vitro. In all these versatile approaches, ketamine and (2R,6R)-HNK reduced glutamate release in a manner which could be blocked by AMPA receptor antagonism. Antagonism of adenosine A1 receptors, which are almost exclusively expressed at nerve terminals, also counteracted ketamine’s effect on glutamate release and presynaptic activity. Signal transduction studies in primary neuronal cultures demonstrated that ketamine reduced P-T286-CamKII and P-S9-Synapsin, which correlated with decreased synaptic vesicle recycling. Moreover, systemic administration of A1R antagonist counteracted the antidepressant-like actions of ketamine and (2R,6R)-HNK in the forced swim test. To conclude, by studying neuronally released glutamate, we identified a novel retrograde adenosinergic feedback mechanism that mediate inhibitory actions of ketamine on glutamate release that may contribute to its rapid antidepressant action.
Highlights
Major depressive disorder (MDD) is a leading cause of disability worldwide
Ketamine and (2R, 6R)-HNK exert acute reduction of glutamate release in vivo To examine the effect of (R, S)-ketamine and (2 R, 6 R)-HNK on presynaptic glutamate release we employed Fast Analytic Sensing Technology (FAST) technology to directly assess glutamate levels in brain regions associated with MDD
Most of previous publications linked acute antidepressant effect of ketamine to drug-induced glutamate surge [21, 30, 55] probably due to selective inhibition of N-methyl-D-aspartate receptor (NMDAR) located on GABAeric interneurons [14, 24, 56]
Summary
Major depressive disorder (MDD) is a leading cause of disability worldwide. The most prescribed antidepressant medications target monoamine neurotransmitter function, but their therapeutic response requires treatment for 2–3 months and they are ineffective in >30% of patients [1]. Contrariwise, a single systemic dose of ketamine, a N-methyl-D-aspartate receptor (NMDAR) antagonist [2] can rapidly reduce suicidal ideation and produce an antidepressant effect even in MDD patients who are resistant to monoamine-based antidepressants [3,4,5]. S-ketamine is approved for clinical use in the form of nasal spray [6]. Its usage is limited by adverse events which include psychotomimetic and dissociative symptoms along with abuse liability. Understanding the mechanisms of ketamine’s rapid-onset antidepressant action may aid the development of novel antidepressant medications that have fewer side effects
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