Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors

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.

Imaging the effect of ketamine on synaptic density (SV2A) in the living brain

“…For example, the increase in glutamate-glutamine cycling, which may reflect changes in presynaptic release machinery, is time-limited, and may even be decreased at the 24-hour timepoint 64 , such that the major sustained change could be occurring post-synaptically. The effects of ketamine on glutamate release and presynaptic release machinery appears to be much more nuanced than previously thought, with recent evidence showing that ketamine reduces glutamate release and synaptic vesicle recycling in rodents 65 , in line with earlier work suggesting that ketamine administration reduces the number of vesicles 62 . If ketamine reduces synaptic vesicle recycling, we might expect to observe lower SV2A density following ketamine administration.…”

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

“…Differently, Stan et al (2014) , by using in vivo measurement with microelectrode array, found that systemic subanesthetic S-ketamine reduced glutamate release in the subiculum, and local application reduced release in the subiculum and PL-PFC. More recently, by using an in vitro and in vivo combined approach (Fast Analytic Sensing Technology, FAST), ketamine was reported to reduce presynaptic glutamate neurotransmission in the subiculum and PL-PFC, with mechanisms implying retrograde stimulation of presynaptic adenosine A1 receptors ( Lazarevic et al, 2021 ).…”

Pathophysiology and Current Drug Treatments for Post-Stroke Depression: A Review

“…Increased excitation of the cells heightens the risk of brain cell damage or death. Therefore, ketamine stabilizes the glutamatergic system, whose dysfunction causes mood disorders, including PSD [ 110 ].…”