Interaction between Mesocortical and Mesothalamic Catecholaminergic Transmissions Associated with NMDA Receptor in the Locus Coeruleus

Abstract

<jats:p>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.</jats:p>

Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor

“…The MDTN receives inputs from various cortical and subcortical regions associated with learning, memory, emotion, and perceptual integration [ 6 , 14 , 35 , 45 , 53 , 74 , 75 , 76 ]. The MDTN projects glutamatergic terminals to a number of cortical regions, such as the mPFC, insula, orbitofrontal cortex (OFC), and basal ganglia [ 6 , 14 , 35 , 45 , 53 , 54 , 55 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. In spite of being feeble in rodents, the properties of thalamocortical glutamatergic transmission have been shown to translate from rodents to humans in terms of cognitive function [ 73 , 86 ].…”

“…It has been well established that the MDTN receives mainly inhibitory GABAergic inhibition from the RTN, which is activated by noradrenergic, serotonergic, and glutamatergic inputs via α1 adrenoceptor, 5-HT7R, and NMDA/glutamate receptors [ 6 , 35 , 45 , 53 , 54 , 55 , 78 ]. NMDA/glutamate receptor inhibitor, MK801, and ketamine/esketamine drastically enhanced thalamocortical glutamatergic transmission via intra-thalamic GABAergic disinhibition [ 6 , 35 , 54 , 55 , 56 , 82 , 87 ].…”

“…According to these previous reports, in the present study, to study the subchronic effects of lurasidone, vortioxetine, and escitalopram, rats were subcutaneously administered lurasidone (3 mg/kg/day), vortioxetine (2.5 mg/kg/day), or escitalopram (5 mg/kg/day) for 3 or 7 days using an osmotic pump (2ML_1, Alzet, Cupertino, CA, USA). The present study used concentrations of AS19 (5 μM), SB269970 (10 μM), and MK801 (10 μM) according to previous studies [ 6 , 35 , 45 , 54 , 96 ]…”

“…5-HT7R is highly expressed in regions relevant to cognitive function, such as the thalamus, as well as in the hypothalamus, hippocampus, prefrontal cortex, striatal complex, amygdala, and dorsal raphe nucleus [ 45 , 46 , 47 , 48 ]. Over the last two decades, preclinical studies have accumulated various findings, highlighting 5-HT7R as a key player in the regulation of mood, memory processing, cognition, and emotional perception, as demonstrated by various experiments using selective 5-HT7R antagonists and 5-HT7R knock-out mice models [ 28 , 49 ].…”

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

“…Indeed, the deficit/disruption of MDTN exhibited deficits in the regulation of learning, memory, emotion, and perceptual integration [ 97 , 98 , 99 , 100 , 101 ]. Contrary, the tonic activation of the thalamocortical glutamatergic pathway in experimental animal models of schizophrenia, attention-deficit hyperactivity disorder, and autism has been observed [ 76 , 77 , 84 , 85 , 94 , 102 , 103 , 104 , 105 , 106 , 107 ].…”