Abstract
Noncompetitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonists contribute to the pathophysiology of schizophrenia and mood disorders but improve monoaminergic antidepressant-resistant mood disorder and suicidal ideation. The mechanisms of the double-edged sword clinical action of NMDAR antagonists remained to be clarified. The present study determined the interaction between the NMDAR antagonist (MK801), α1 adrenoceptor antagonist (prazosin), and α2A adrenoceptor agonist (guanfacine) on mesocortical and mesothalamic catecholaminergic transmission, and thalamocortical glutamatergic transmission using multiprobe microdialysis. The inhibition of NMDAR in the locus coeruleus (LC) by local MK801 administration enhanced both the mesocortical noradrenergic and catecholaminergic coreleasing (norepinephrine and dopamine) transmissions. The mesothalamic noradrenergic transmission was also enhanced by local MK801 administration in the LC. These mesocortical and mesothalamic transmissions were activated by intra-LC disinhibition of transmission of γ-aminobutyric acid (GABA) via NMDAR inhibition. Contrastingly, activated mesothalamic noradrenergic transmission by MK801 enhanced intrathalamic GABAergic inhibition via the α1 adrenoceptor, resulting in the suppression of thalamocortical glutamatergic transmission. The thalamocortical glutamatergic terminal stimulated the presynaptically mesocortical catecholaminergic coreleasing terminal in the superficial cortical layers, but did not have contact with the mesocortical selective noradrenergic terminal (which projected terminals to deeper cortical layers). Furthermore, the α2A adrenoceptor suppressed the mesocortical and mesothalamic noradrenergic transmissions somatodendritically in the LC and presynaptically/somatodendritically in the reticular thalamic nucleus (RTN). These discrepancies between the noradrenergic and catecholaminergic transmissions in the mesocortical and mesothalamic pathways probably constitute the double-edged sword clinical action of noncompetitive NMDAR antagonists.
Highlights
The impact of N-methyl-D-aspartate/glutamate receptor (NMDAR) modulation has been a fundamental psychopharmacological discussion, since (S)-ketamine was approved by the Food and Drug Administration (FDA) in early 2019 as a rapid-acting antidepressant for the treatment of major depressive disorders [1]
NAfatenrdthMeDsTtaNbilwiseartieomn aoifnttraainnsemdiwtteitrhleMveRlSinalpoenrefudsuartein, gpeSrtfuudsiyo_n1. medium in the locus coeruleus (LC) was switched to the same modified Ringer’s solution (MRS) containing with MK801 (1 or 5 μM) for 180 min
Further complex considerations are required regarding the relationship between mesocortical catecholaminergic coreleasing transmission and cognition. We demonstrated that both local and systemic administrations of MK801 enhanced the thalamocortical glutamatergic transmission concentration dose-dependently [28,29,35]; the MK801-induced activation of thalamocortical glutamatergic transmission is compensated by antipsychotics, clozapine, aripiprazole, and lurasidone [26,27,30,31]
Summary
The impact of N-methyl-D-aspartate/glutamate receptor (NMDAR) modulation has been a fundamental psychopharmacological discussion, since (S)-ketamine was approved by the Food and Drug Administration (FDA) in early 2019 as a rapid-acting antidepressant for the treatment of major depressive disorders [1]. Ketamine dose-dependently increases norepinephrine release in the medial prefrontal cortex, but clonidine inhibits ketamine-induced norepinephrine release via the activation of the presynaptic α2 adrenoceptor [22,23] These findings suggest that ketamine enhances noradrenergic transmission similar to serotonin/norepinephrine transporter inhibitors. Norepinephrine transporter inhibiting antidepressants and ketamine suppress and enhance neuronal activities in the LC, respectively [24,25] These contradictive demonstrations between electrophysiological and microdialysis studies suggest that the LC is probably one of the major target regions of the clinical action of ketamine, but the norepinephrine transporter inhibition probably cannot play an important role in the stimulatory effects of ketamine on noradrenergic transmission
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