Abstract
PurposeIn 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.MethodsHere 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.ResultsFor 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.ConclusionsIn 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.
Highlights
In vivo microdialysis methods have been developed to study the quantity of the chemical composition of interstitial tissue fluids
Numerous microdialysis studies focus on amino acids, in particular glutamate and glutamate and γ-aminobutyric acid (GABA), as these neurotransmitters are the key players in the excitatory and inhibitory network of the central nervous system (CNS) and are involved in a variety of neuropsychiatric diseases, including substance abuse and alcohol use disorders (Kalivas, 2009; Spanagel, 2009)
Several studies employing brain microdialysis experiments in alcohol-dependent animals have shown augmented extracellular glutamate levels in various brain sites that correlate with the intensity of the withdrawal response (Rossetti and Carboni, 1995; Gass and Olive, 2008; Gass et al, 2011)
Summary
In vivo microdialysis methods have been developed to study the quantity of the chemical composition of interstitial tissue fluids. The NMDA receptor is a ligand-gated ion channel with a heteromeric assembly of NR1, NR2 (A-D), and NR3 subunits, and genetic variants that affect the vulnerability to alcohol dependence within the genes encoding these subunits have been identified (Schumann et al, 2008; Domart et al, 2012; Tsai and Coyle, 2012) In addition to this direct interaction with the NMDA receptor, acute alcohol administration affects glutamatergic neurons at the synaptic and cellular level and thereby releases glutamate. Several studies employing brain microdialysis experiments in alcohol-dependent animals have shown augmented extracellular glutamate levels in various brain sites that correlate with the intensity of the withdrawal response (Rossetti and Carboni, 1995; Gass and Olive, 2008; Gass et al, 2011). This finding translates into the human situation, as alcoholics undergoing acute withdrawal exhibit increased glutamate brain levels, as measured by magnetic resonance spectroscopy (Hermann et al, 2012)
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