Gintonin attenuates depressive-like behaviors associated with alcohol withdrawal in mice

Kim, Hyeonjoong; Park, Sang-Deuk; Lee, Ra Mi; Lee, Byung-Hwan; Choi, Sun-Hye; Hwang, Sung‐Hee; Rhim, Hyewhon; Kim, Hyoung‐Chun; Nah, Seung‐Yeol

doi:10.1016/j.jad.2017.03.026

Cited by 33 publications

(22 citation statements)

References 38 publications

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“…Similarly, in the FST, EtOH-exposed mice exhibited greater depressive-like behavior (i.e., greater time spent immobile) than air-exposed controls overall, and specifically on post-Tx days 13 and 20. Together, the SPT and FST data suggest that CIE vapor exposure induced a delayed and sustained display of behavioral depression, which is consistent with previous work employing either long-term free-choice drinking or maintenance on an EtOH liquid diet to induce tolerance (Gong et al, 2017;Holleran et al, 2016;Kim et al, 2017;Pang et al, 2013;Roni and Rahman, 2017;Stevenson et al, 2009). Thus, our data provide novel evidence for the ability of CIE vapor exposure to induce delayed emergence and sustained expression of depressive-like behavior during long-term forced abstinence in mice.…”

Section: Discussionsupporting

confidence: 89%

Affective Disruption During Forced Ethanol Abstinence in C57BL/6J and C57BL/6NJ Mice

Hartmann

Haney

Smith

et al. 2020

Alcoholism Clin & Exp Res

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Background: In alcohol-dependent individuals, acute alcohol withdrawal results in severe physiological disruption, including potentially lethal central nervous system hyperexcitability. Although benzodiazepines successfully mitigate such symptoms, this treatment does not significantly reduce recidivism rates in postdependent individuals. Instead, persistent affective disturbances that often emerge weeks to months after initial detoxification appear to play a significant role in relapse risk; however, it remains unclear whether genetic predispositions contribute to their emergence, severity, and/or duration. Interestingly, significant genotypic and phenotypic differences have been observed among distinct C57BL/6 (B6) substrains, and, in particular, C57BL/6J (B6J) mice have been found to reliably exhibit higher voluntary ethanol (EtOH) intake and EtOH preference compared to several C57BL/6N (B6N)-derived substrains. To date, however, B6 substrains have not been directly compared on measures of acute withdrawal severity or affective-behavioral disruption during extended abstinence. Methods: Male and female B6J and B6NJ mice were exposed to either a 7-day chronic intermittent EtOH vapor (CIE) protocol or to ordinary room air in inhalation chambers. Subsequently, blood EtOH concentrations and handling-induced convulsions were evaluated during acute withdrawal, and mice were then tested weekly for affective behavior on the sucrose preference test, light-dark box test, and forced swim test throughout 4 weeks of (forced) abstinence. Results: Despite documented differences in voluntary EtOH intake between these substrains, we found little evidence for substrain differences in either acute withdrawal or long-term abstinence between B6J and B6NJ mice. Conclusions: In B6J and B6NJ mice, both the acute and long-term sequelae of EtOH withdrawal are dependent on largely nonoverlapping gene networks relative to those underlying voluntary EtOH drinking.

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Section: Discussionsupporting

confidence: 89%

Affective Disruption During Forced Ethanol Abstinence in C57BL/6J and C57BL/6NJ Mice

Hartmann

Haney

Smith

et al. 2020

Alcoholism Clin & Exp Res

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“…Notably, pharmacological manipulation of the LPA 1 receptor has also been linked to various mood-related effects ( Castilla-Ortega et al, 2014 ; Kim et al, 2017 ). Interestingly, some of the effects of LPA 1 receptor antagonism by Ki16425 mimic the behavioural features of maLPA 1 -null mice in fear extinction tests ( Pedraza et al, 2014 ), and brain and behavioural impairments associated with alcohol consumption ( Castilla-Ortega et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity

Moreno‐Fernández

Nieto-Quero

Gómez-Salas

et al. 2018

Disease Models &Amp; Mechanisms

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Animal models of psychopathology are particularly useful for studying the neurobiology of depression and characterising the subtypes. Recently, our group was the first to identify a possible relationship between the LPA1 receptor and a mixed anxiety-depression phenotype. Specifically, maLPA1-null mice exhibited a phenotype characterised by depressive and anxious features. However, the constitutive lack of the gene encoding the LPA1 receptor (Lpar1) can induce compensatory mechanisms that might have resulted in the observed deficits. Therefore, in the present study, we have compared the impact of permanent loss and acute pharmacological inhibition of the LPA1 receptor on despair-like behaviours and on the functional brain map associated with these behaviours, as well as on the degree of functional connectivity among structures. Although the antagonist (intracerebroventricularly administered Ki16425) mimicked some, but not all, effects of genetic deletion of the LPA1 receptor on the results of behavioural tests and engaged different brain circuits, both treatments induced depression-like behaviours with an agitation component that was linked to functional changes in key brain regions involved in the stress response and emotional regulation. In addition, both Ki16425 treatment and LPA1 receptor deletion modified the functional brain maps in a way similar to the changes observed in depressed patients. In summary, the pharmacological and genetic approaches could ultimately assist in dissecting the function of the LPA1 receptor in emotional regulation and brain responses, and a combination of those approaches might provide researchers with an opportunity to develop useful drugs that target the LPA1 receptor as treatments for depression, mainly the anxious subtype.

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“…LPI and GPR55 are implicated as potential key modulators of stress responses, depression, motor functions, and memory in the central nervous system, since GPR55 is highly expressed in the cortex, hippocampus, striatum, and spinal cord [22][23][24]. In previous studies, we showed that gintonin attenuated depressive behaviors, enhanced motor function performance, and enhanced hippocampal-dependent cognitive functions [11,35,36]. Although we did not demonstrate that these gintonin-mediated effects on the central nervous system were directly achieved via GPR55, gintonin LPIs and LPAs might play important roles in various brain functions.…”

Section: Discussionmentioning

confidence: 82%

“…We reported that gintonin exerted diverse cellular effects in vitro through LPA receptor activation, including transient intracellular calcium mobilization, morphological changes, enhancement of proliferation and migration, vascular development, and neurite retraction [5][6][7][8][9]. Gintonin has also consistently shown memory improvement, hippocampal cell proliferation, and neurodegenerative disease antagonism in animal models [5,6,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Ginseng Gintonin Contains Ligands for GPR40 and GPR55

et al. 2020

Self Cite

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Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.

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Gintonin attenuates depressive-like behaviors associated with alcohol withdrawal in mice

Cited by 33 publications

References 38 publications

Affective Disruption During Forced Ethanol Abstinence in C57BL/6J and C57BL/6NJ Mice

Affective Disruption During Forced Ethanol Abstinence in C57BL/6J and C57BL/6NJ Mice

Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity

Ginseng Gintonin Contains Ligands for GPR40 and GPR55

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