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Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis.

Fliegel S, Brand I, Spanagel R, Noori HR - In Silico Pharmacol (2013)

Bottom Line: Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve.In summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release.Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany.

ABSTRACT

Purpose: In recent years in vivo microdialysis has become an important method in research studies investigating the alterations of neurotransmitters in the extracellular fluid of the brain. Based on the major involvement of glutamate and γ-aminobutyric acid (GABA) in mediating a variety of alcohol effects in the mammalian brain, numerous microdialysis studies have focused on the dynamical behavior of these systems in response to alcohol.

Methods: Here we performed multiple meta-analyses on published datasets from the rat brain: (i) we studied basal extracellular concentrations of glutamate and GABA in brain regions that belong to a neurocircuitry involved in neuropsychiatric diseases, especially in alcoholism (Noori et al., Addict Biol 17:827-864, 2012); (ii) we examined the effect of acute ethanol administration on glutamate and GABA levels within this network and (iii) we studied alcohol withdrawal-induced alterations in glutamate and GABA levels within this neurocircuitry.

Results: For extraction of basal concentrations of these neurotransmitters, datasets of 6932 rats were analyzed and the absolute basal glutamate and GABA levels were estimated for 18 different brain sites. In response to different doses of acute ethanol administration, datasets of 529 rats were analyzed and a non-linear dose response (glutamate and GABA release) relationship was observed in several brain sites. Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve. Finally, regression analysis of 11 published reports employing brain microdialysis experiments in 104 alcohol-dependent rats reveals very consistent augmented extracellular glutamate and GABA levels in various brain sites that correlate with the intensity of the withdrawal response were identified.

Conclusions: In summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release. Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.

No MeSH data available.


Related in: MedlinePlus

Forest-plot of the basal value of glutamate in the nucleus accumbens as measured in 28 experiments, ordered by year of publication. Row 1 indicates the weighted average basal value and its standard error of mean (±SEM). The vertical line extends the weighted mean in order to compare the extracted data. 2 Dahchour et al. (1994); 3 Selim and Bradberry (1996); 4 You et al. (1998); 5 Dalley et al. (1999); 6,7,8 Segovia et al. (1999); 9 Fu et al. (2000); 10 Quertemont et al. (2000); 11 Dawson et al. (2001); 12 Giorgetti et al. (2001); 13,14 Hemmati et al. (2001); 15 You et al. (2001); 16 Saulskaya and Mikhailova (2002); 17 Zangen and Hyodo (2002); 18 Hotsenpiller and Wolf (2003); 19 Mikhailova (2003); 20 Xi et al. (2003a); 21 Quarta et al. (2004); 22 Saulskaya and Soloviova (2004); 23 Shou et al. (2004); 24 Saul'skaya and Mikhailova (2005); 25 Ito et al. (2006); 26 Lallemand et al. (2006); 27 Hernandez (2008); 28 Huang et al. (2008); 29 Li et al. (2010b).
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Fig2: Forest-plot of the basal value of glutamate in the nucleus accumbens as measured in 28 experiments, ordered by year of publication. Row 1 indicates the weighted average basal value and its standard error of mean (±SEM). The vertical line extends the weighted mean in order to compare the extracted data. 2 Dahchour et al. (1994); 3 Selim and Bradberry (1996); 4 You et al. (1998); 5 Dalley et al. (1999); 6,7,8 Segovia et al. (1999); 9 Fu et al. (2000); 10 Quertemont et al. (2000); 11 Dawson et al. (2001); 12 Giorgetti et al. (2001); 13,14 Hemmati et al. (2001); 15 You et al. (2001); 16 Saulskaya and Mikhailova (2002); 17 Zangen and Hyodo (2002); 18 Hotsenpiller and Wolf (2003); 19 Mikhailova (2003); 20 Xi et al. (2003a); 21 Quarta et al. (2004); 22 Saulskaya and Soloviova (2004); 23 Shou et al. (2004); 24 Saul'skaya and Mikhailova (2005); 25 Ito et al. (2006); 26 Lallemand et al. (2006); 27 Hernandez (2008); 28 Huang et al. (2008); 29 Li et al. (2010b).

Mentions: Literature search revealed 245 publications that fulfilled the selection criteria for baseline values of glutamate and GABA. Out of these 43.3% were published before the year 2000, 51.8% between 2000 and 2010 and 4.5% after 2010. Altogether 6932 animals were used in these experiments. Average basal values, as well as the statistical distribution (i.e., median, maximum and minimum) are represented in Table 1 (glutamate) and Table 2 (GABA) for 18 different brain regions respectively (for the habenula no data could be retrieved from Pubmed). The forest plots (Figures 1 and 2) represent the basal values of glutamate in the PFC and the NAc, respectively. Rapid microelectrode measurements of glutamate in the PFC (Hascup et al., 2010), glutamate measurements with oxidase-coated biosensors in the AMY and NAc (Gass et al., 2011) as well as a variety of control experiments (Timmerman and Westerink, 1997; Sun et al., 2011) suggest the neuronal origin of these concentrations.Figure 1


Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis.

Fliegel S, Brand I, Spanagel R, Noori HR - In Silico Pharmacol (2013)

Forest-plot of the basal value of glutamate in the nucleus accumbens as measured in 28 experiments, ordered by year of publication. Row 1 indicates the weighted average basal value and its standard error of mean (±SEM). The vertical line extends the weighted mean in order to compare the extracted data. 2 Dahchour et al. (1994); 3 Selim and Bradberry (1996); 4 You et al. (1998); 5 Dalley et al. (1999); 6,7,8 Segovia et al. (1999); 9 Fu et al. (2000); 10 Quertemont et al. (2000); 11 Dawson et al. (2001); 12 Giorgetti et al. (2001); 13,14 Hemmati et al. (2001); 15 You et al. (2001); 16 Saulskaya and Mikhailova (2002); 17 Zangen and Hyodo (2002); 18 Hotsenpiller and Wolf (2003); 19 Mikhailova (2003); 20 Xi et al. (2003a); 21 Quarta et al. (2004); 22 Saulskaya and Soloviova (2004); 23 Shou et al. (2004); 24 Saul'skaya and Mikhailova (2005); 25 Ito et al. (2006); 26 Lallemand et al. (2006); 27 Hernandez (2008); 28 Huang et al. (2008); 29 Li et al. (2010b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230485&req=5

Fig2: Forest-plot of the basal value of glutamate in the nucleus accumbens as measured in 28 experiments, ordered by year of publication. Row 1 indicates the weighted average basal value and its standard error of mean (±SEM). The vertical line extends the weighted mean in order to compare the extracted data. 2 Dahchour et al. (1994); 3 Selim and Bradberry (1996); 4 You et al. (1998); 5 Dalley et al. (1999); 6,7,8 Segovia et al. (1999); 9 Fu et al. (2000); 10 Quertemont et al. (2000); 11 Dawson et al. (2001); 12 Giorgetti et al. (2001); 13,14 Hemmati et al. (2001); 15 You et al. (2001); 16 Saulskaya and Mikhailova (2002); 17 Zangen and Hyodo (2002); 18 Hotsenpiller and Wolf (2003); 19 Mikhailova (2003); 20 Xi et al. (2003a); 21 Quarta et al. (2004); 22 Saulskaya and Soloviova (2004); 23 Shou et al. (2004); 24 Saul'skaya and Mikhailova (2005); 25 Ito et al. (2006); 26 Lallemand et al. (2006); 27 Hernandez (2008); 28 Huang et al. (2008); 29 Li et al. (2010b).
Mentions: Literature search revealed 245 publications that fulfilled the selection criteria for baseline values of glutamate and GABA. Out of these 43.3% were published before the year 2000, 51.8% between 2000 and 2010 and 4.5% after 2010. Altogether 6932 animals were used in these experiments. Average basal values, as well as the statistical distribution (i.e., median, maximum and minimum) are represented in Table 1 (glutamate) and Table 2 (GABA) for 18 different brain regions respectively (for the habenula no data could be retrieved from Pubmed). The forest plots (Figures 1 and 2) represent the basal values of glutamate in the PFC and the NAc, respectively. Rapid microelectrode measurements of glutamate in the PFC (Hascup et al., 2010), glutamate measurements with oxidase-coated biosensors in the AMY and NAc (Gass et al., 2011) as well as a variety of control experiments (Timmerman and Westerink, 1997; Sun et al., 2011) suggest the neuronal origin of these concentrations.Figure 1

Bottom Line: Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve.In summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release.Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.

View Article: PubMed Central - PubMed

Affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany.

ABSTRACT

Purpose: In recent years in vivo microdialysis has become an important method in research studies investigating the alterations of neurotransmitters in the extracellular fluid of the brain. Based on the major involvement of glutamate and γ-aminobutyric acid (GABA) in mediating a variety of alcohol effects in the mammalian brain, numerous microdialysis studies have focused on the dynamical behavior of these systems in response to alcohol.

Methods: Here we performed multiple meta-analyses on published datasets from the rat brain: (i) we studied basal extracellular concentrations of glutamate and GABA in brain regions that belong to a neurocircuitry involved in neuropsychiatric diseases, especially in alcoholism (Noori et al., Addict Biol 17:827-864, 2012); (ii) we examined the effect of acute ethanol administration on glutamate and GABA levels within this network and (iii) we studied alcohol withdrawal-induced alterations in glutamate and GABA levels within this neurocircuitry.

Results: For extraction of basal concentrations of these neurotransmitters, datasets of 6932 rats were analyzed and the absolute basal glutamate and GABA levels were estimated for 18 different brain sites. In response to different doses of acute ethanol administration, datasets of 529 rats were analyzed and a non-linear dose response (glutamate and GABA release) relationship was observed in several brain sites. Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve. Finally, regression analysis of 11 published reports employing brain microdialysis experiments in 104 alcohol-dependent rats reveals very consistent augmented extracellular glutamate and GABA levels in various brain sites that correlate with the intensity of the withdrawal response were identified.

Conclusions: In summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release. Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.

No MeSH data available.


Related in: MedlinePlus