Carrier‐mediated high affinity uptake system for histamine in astroglial and cerebral endothelial cells

Huszti, Z.

doi:10.1002/(sici)1097-4547(19980301)51:5<551::aid-jnr1>3.3.co;2-g

Cited by 3 publications

(4 citation statements)

References 37 publications

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“…C, Evoked hippocampal serotonin control (gray) and 701 min post-ESCIT administration (red; 10 mg/kg) in Met172 mice (n = 5; i) and WT (n = 4; ii) with a stimulation marked by a green box below at 5-7 s. Control evoked hypothalamic histamine (blue), and 60 min post-ESCIT administration (green; 10 mg/kg) in Met172 mice (iii) and WT mice (n = 4 each; iv). (Huszti, 1998(Huszti, , 2003, a histamine-specific transporter has not been identified (Hough, 1988;Brown et al, 2001). Histamine inactivation is thought to be via histamine Nmethyltransferase (HNMT; White, 1960;Schayer and Reily, 1973;Pollard et al, 1974;Takemura et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin

et al. 2021

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Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter to correct a presumed deficit in extracellular serotonin signaling during depression. These agents bring clinical relief to many who take them; however, a significant and growing number of individuals are resistant to SSRIs. There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown. In this work, we use fast in vivo serotonin measurement tools to investigate the nexus between serotonin, inflammation, and SSRIs. Upon acute systemic lipopolysaccharide (LPS) administration in male and female mice, we find robust decreases in extracellular serotonin in the mouse hippocampus. We show that these decreased serotonin levels are supported by increased histamine activity (because of inflammation), acting on inhibitory histamine H3 heteroreceptors on serotonin terminals. Importantly, under LPS-induced histamine increase, the ability of escitalopram to augment extracellular serotonin is impaired because of an offtarget action of escitalopram to inhibit histamine reuptake. Finally, we show that a functional decrease in histamine synthesis boosts the ability of escitalopram to increase extracellular serotonin levels following LPS. This work reveals a profound effect of inflammation on brain chemistry, specifically the rapidity of inflammation-induced decreased extracellular serotonin, and points the spotlight at a potentially critical player in the pathology of depression, histamine. The serotonin/histamine homeostasis thus, may be a crucial new avenue in improving serotonin-based treatments for depression.

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Section: Discussionmentioning

confidence: 99%

Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin

et al. 2021

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“…Rat astrocytes were capable of significant histamine uptake, but rat synaptosomes did not have histamine transport activity. In addition to these in vitro experiments, Huszti et al demonstrated that astrocytes played a crucial role in the clearance of brain histamine in vivo (Huszti, 1998(Huszti, , 2003Huszti et al, 1998). In addition to these in vitro experiments, Huszti et al demonstrated that astrocytes played a crucial role in the clearance of brain histamine in vivo (Huszti, 1998(Huszti, , 2003Huszti et al, 1998).…”

Section: Introductionmentioning

confidence: 98%

“…The total activity of histamine N-methyltransferase (HNMT), which metabolizes histamine to inactive 1methylhistamine, was found to be much higher in astrocytes than in synaptosomes (Rafalowska et al, 1987). In addition to these in vitro experiments, Huszti et al demonstrated that astrocytes played a crucial role in the clearance of brain histamine in vivo (Huszti, 1998(Huszti, , 2003Huszti et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of histamine clearance by primary human astrocytes

Yoshikawa

Naganuma

Iida

et al. 2013

Glia

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Histamine clearance is an essential process for avoiding excessive histaminergic neuronal activity. Previous studies using rodents revealed the predominant role of astrocytes in brain histamine clearance. However, the molecular mechanism of histamine clearance has remained unclear. We detected histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, in primary human astrocytes and the astrocytes of human brain specimens. Immunocytochemical analysis and subcellular fractionation assays revealed that active HNMT localized to the cytosol, suggesting that histamine transport into the cytosol is crucial for histamine inactivation. We showed that primary human astrocytes transported histamine in a time-dependent manner. Kinetics analysis showed that two low-affinity transporters were involved in histamine transport. Histamine uptake by primary human astrocytes was not dependent on the extracellular Na(+) /Cl(-) concentration. Histamine is reported to be a substrate for three low-affinity and Na(+) /Cl(-) -independent transporters: organic cation transporter 2 (OCT2), OCT3, and plasma membrane monoamine transporter (PMAT). RT-PCR analysis revealed that OCT3 and PMAT were expressed in primary human astrocytes. Immunohistochemistry confirmed OCT3 and PMAT expression in the astrocytes of human brain specimens. Drug inhibition assays and gene knockdown assays revealed the major contribution of PMAT and the minor contribution of OCT3 to histamine transport. The present study demonstrates for the first time that the molecular mechanism of histamine clearance is by primary human astrocytes. These findings might indicate that PMAT, OCT3 and HNMT in human astrocytes play a role in the regulation of extraneuronal histamine concentration and the activities of histaminergic neurons.

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“…Among glial cells astrocytes have been proposed to be the main histamine inactivation site [6]. Reports from Huszti´s laboratory described bidirectional [7][8][9] histamine uptake into cultured glial cells prepared from embryonic chicks [7] and neonatal rats [8][9][10] which was Na + -but not Cl --dependent [11]. Glial cells were also found to be involved in the continuous removal of neuronal histamine from the synaptic cleft in in vivo conditions [12].…”

Section: Introductionmentioning

confidence: 99%