Limits...
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

Dose-dependent ethanol induced changes of extracellular glutamate concentrations (nM) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4230485&req=5

Fig3: Dose-dependent ethanol induced changes of extracellular glutamate concentrations (nM) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of rats.

Mentions: Our literature search revealed 17 publications that were in agreement with our selection criteria for acute ethanol exposure. Out of these, 66 values were extracted. Altogether 529 animals were used in the experiments. Observation of seven brain regions fulfilled the selection criteria: AMY, GP, HC, NAc, PFC, CPu, and VTA. In general, alcohol was administered via three routes: (i) almost 90% of the experiments used intraperitoneal (i.p.) injections in a dose between 0.5 and 3.0 g/kg body weight; (ii) local infusion (100–1000 mM) of alcohol in 8% of the studies; and (iii) the remaining experiments applied ethanol orally (20% ethanol). The average magnitude of increase/decrease comparing to the baseline concentrations (peak % baseline) and the average peak time are presented in the Tables 5 and 6. The correlation analysis shows a non-uniform (region-dependent) interaction between ethanol and the release of glutamate and GABA. In particular, ethanol-induced alterations in glutamate concentrations appear to depend on the network properties such as the connectivity of the brain regions within the neurocircuitry for modelling drug effects. This observation is best reflected in the analysis of the PFC, NAc and CPu (Figure 3). While ethanol increases the glutamate concentrations in the PFC in a dose-dependent fashion, it simultaneously decreases the extracellular levels of glutamate in the NAc and CPu. In contrast GABA concentrations were elevated in the NAc following the same doses of alcohol.Table 5


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)

Dose-dependent ethanol induced changes of extracellular glutamate concentrations (nM) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Dose-dependent ethanol induced changes of extracellular glutamate concentrations (nM) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of rats.
Mentions: Our literature search revealed 17 publications that were in agreement with our selection criteria for acute ethanol exposure. Out of these, 66 values were extracted. Altogether 529 animals were used in the experiments. Observation of seven brain regions fulfilled the selection criteria: AMY, GP, HC, NAc, PFC, CPu, and VTA. In general, alcohol was administered via three routes: (i) almost 90% of the experiments used intraperitoneal (i.p.) injections in a dose between 0.5 and 3.0 g/kg body weight; (ii) local infusion (100–1000 mM) of alcohol in 8% of the studies; and (iii) the remaining experiments applied ethanol orally (20% ethanol). The average magnitude of increase/decrease comparing to the baseline concentrations (peak % baseline) and the average peak time are presented in the Tables 5 and 6. The correlation analysis shows a non-uniform (region-dependent) interaction between ethanol and the release of glutamate and GABA. In particular, ethanol-induced alterations in glutamate concentrations appear to depend on the network properties such as the connectivity of the brain regions within the neurocircuitry for modelling drug effects. This observation is best reflected in the analysis of the PFC, NAc and CPu (Figure 3). While ethanol increases the glutamate concentrations in the PFC in a dose-dependent fashion, it simultaneously decreases the extracellular levels of glutamate in the NAc and CPu. In contrast GABA concentrations were elevated in the NAc following the same doses of alcohol.Table 5

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